|
Cytotoxicity against human SH-SY5Y cells assessed as cell viability after 48 hrs by MTT assay
|
Homo sapiens
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry.
Year : 2010
Volume : 53
Issue : 2
First Page : 616
Last Page : 623
Authors : Colombano G, Travelli C, Galli U, Caldarelli A, Chini MG, Canonico PL, Sorba G, Bifulco G, Tron GC, Genazzani AA.
Abstract : The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 + 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues. The most promising compound displays an IC(50) for cytotoxicity in vitro of 3.8 +/- 0.3 nM and an IC(50) for NAD depletion of 3.0 +/- 0.4 nM. Herein, we strengthen previous data suggesting that this class of compounds induces autophagic cell death. In addition to characterizing this compound and providing a rationale via molecular docking, we reinforce the excellent potential of click chemistry for rapidly generating structure-activity relationships and for drug screening.
|
Cytotoxicity against human SH-SY5Y cells assessed as reduction of total cellular NAD(P) level
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry.
Year : 2010
Volume : 53
Issue : 2
First Page : 616
Last Page : 623
Authors : Colombano G, Travelli C, Galli U, Caldarelli A, Chini MG, Canonico PL, Sorba G, Bifulco G, Tron GC, Genazzani AA.
Abstract : The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 + 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues. The most promising compound displays an IC(50) for cytotoxicity in vitro of 3.8 +/- 0.3 nM and an IC(50) for NAD depletion of 3.0 +/- 0.4 nM. Herein, we strengthen previous data suggesting that this class of compounds induces autophagic cell death. In addition to characterizing this compound and providing a rationale via molecular docking, we reinforce the excellent potential of click chemistry for rapidly generating structure-activity relationships and for drug screening.
|
Cytotoxicity against human HT1080 cells after 6 days by SRB assay
|
Homo sapiens
|
160.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents.
Year : 2011
Volume : 46
Issue : 4
First Page : 1153
Last Page : 1164
Authors : You H, Youn HS, Im I, Bae MH, Lee SK, Ko H, Eom SH, Kim YC.
Abstract : NAmPRTase (PBEF/Visfatin) plays a pivotal role in the salvage pathway of NAD(+) biosynthesis. NAmPRTase has been an attractive target for anti-cancer agents that induce apoptosis of tumor cells via a declining plasma NAD(+) level. In this report, a series of structural analogs of FK866 (1), a known NAmPRTase inhibitor, was synthesized and tested for inhibitory activities against the proliferation of cancer cells and human NAmPRTase. Among them, compound 7 showed similar anti-cancer and enzyme inhibitory activities to compound 1. Further investigation of compound 7 with X-ray analysis revealed a co-crystal structure in complex with human NAmPRTase, suggesting that Asp219 in the active site of the enzyme could contribute to an additional interaction with the pyrrole nitrogen of compound 7.
|
Antitumor activity against human MCF7 cells at 10 uM after 6 days by SRB assay
|
Homo sapiens
|
680.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents.
Year : 2011
Volume : 46
Issue : 4
First Page : 1153
Last Page : 1164
Authors : You H, Youn HS, Im I, Bae MH, Lee SK, Ko H, Eom SH, Kim YC.
Abstract : NAmPRTase (PBEF/Visfatin) plays a pivotal role in the salvage pathway of NAD(+) biosynthesis. NAmPRTase has been an attractive target for anti-cancer agents that induce apoptosis of tumor cells via a declining plasma NAD(+) level. In this report, a series of structural analogs of FK866 (1), a known NAmPRTase inhibitor, was synthesized and tested for inhibitory activities against the proliferation of cancer cells and human NAmPRTase. Among them, compound 7 showed similar anti-cancer and enzyme inhibitory activities to compound 1. Further investigation of compound 7 with X-ray analysis revealed a co-crystal structure in complex with human NAmPRTase, suggesting that Asp219 in the active site of the enzyme could contribute to an additional interaction with the pyrrole nitrogen of compound 7.
|
Cytotoxicity against human A549 cells after 6 days by SRB assay
|
Homo sapiens
|
160.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents.
Year : 2011
Volume : 46
Issue : 4
First Page : 1153
Last Page : 1164
Authors : You H, Youn HS, Im I, Bae MH, Lee SK, Ko H, Eom SH, Kim YC.
Abstract : NAmPRTase (PBEF/Visfatin) plays a pivotal role in the salvage pathway of NAD(+) biosynthesis. NAmPRTase has been an attractive target for anti-cancer agents that induce apoptosis of tumor cells via a declining plasma NAD(+) level. In this report, a series of structural analogs of FK866 (1), a known NAmPRTase inhibitor, was synthesized and tested for inhibitory activities against the proliferation of cancer cells and human NAmPRTase. Among them, compound 7 showed similar anti-cancer and enzyme inhibitory activities to compound 1. Further investigation of compound 7 with X-ray analysis revealed a co-crystal structure in complex with human NAmPRTase, suggesting that Asp219 in the active site of the enzyme could contribute to an additional interaction with the pyrrole nitrogen of compound 7.
|
Cytotoxicity against human HCT116 cells after 6 days by SRB assay
|
Homo sapiens
|
160.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents.
Year : 2011
Volume : 46
Issue : 4
First Page : 1153
Last Page : 1164
Authors : You H, Youn HS, Im I, Bae MH, Lee SK, Ko H, Eom SH, Kim YC.
Abstract : NAmPRTase (PBEF/Visfatin) plays a pivotal role in the salvage pathway of NAD(+) biosynthesis. NAmPRTase has been an attractive target for anti-cancer agents that induce apoptosis of tumor cells via a declining plasma NAD(+) level. In this report, a series of structural analogs of FK866 (1), a known NAmPRTase inhibitor, was synthesized and tested for inhibitory activities against the proliferation of cancer cells and human NAmPRTase. Among them, compound 7 showed similar anti-cancer and enzyme inhibitory activities to compound 1. Further investigation of compound 7 with X-ray analysis revealed a co-crystal structure in complex with human NAmPRTase, suggesting that Asp219 in the active site of the enzyme could contribute to an additional interaction with the pyrrole nitrogen of compound 7.
|
Cytotoxicity against human SNU638 cells after 6 days by SRB assay
|
Homo sapiens
|
160.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents.
Year : 2011
Volume : 46
Issue : 4
First Page : 1153
Last Page : 1164
Authors : You H, Youn HS, Im I, Bae MH, Lee SK, Ko H, Eom SH, Kim YC.
Abstract : NAmPRTase (PBEF/Visfatin) plays a pivotal role in the salvage pathway of NAD(+) biosynthesis. NAmPRTase has been an attractive target for anti-cancer agents that induce apoptosis of tumor cells via a declining plasma NAD(+) level. In this report, a series of structural analogs of FK866 (1), a known NAmPRTase inhibitor, was synthesized and tested for inhibitory activities against the proliferation of cancer cells and human NAmPRTase. Among them, compound 7 showed similar anti-cancer and enzyme inhibitory activities to compound 1. Further investigation of compound 7 with X-ray analysis revealed a co-crystal structure in complex with human NAmPRTase, suggesting that Asp219 in the active site of the enzyme could contribute to an additional interaction with the pyrrole nitrogen of compound 7.
|
Cytotoxicity against human A2780 cells after 72 hrs by SRB assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
Year : 2013
Volume : 56
Issue : 12
First Page : 4921
Last Page : 4937
Authors : Zheng X, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Oh A, Wang W, Zak M, Gunzner-Toste J, Zhao G, Yuen PW, Bair KW.
Abstract : Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).
|
Inhibition of Nampt (unknown origin) using NAM/PRPP as substrate preincubated for 15 mins measured after 30 mins
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
Year : 2013
Volume : 56
Issue : 12
First Page : 4921
Last Page : 4937
Authors : Zheng X, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Oh A, Wang W, Zak M, Gunzner-Toste J, Zhao G, Yuen PW, Bair KW.
Abstract : Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).
|
Cytotoxicity against human K562 cells after 96 hrs by MTT assay
|
Homo sapiens
|
7.2
nM
|
|
Journal : J. Med. Chem.
Title : Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6279
Last Page : 6296
Authors : Galli U, Travelli C, Massarotti A, Fakhfouri G, Rahimian R, Tron GC, Genazzani AA.
Abstract : Nicotinamide phoshophoribosyltransferase (NAMPT) plays a key role in the replenishment of the NAD pool in cells. This in turn makes this enzyme an important player in bioenergetics and in the regulation of NAD-using enzymes, such as PARPs and sirtuins. Furthermore, there is now ample evidence that NAMPT is secreted and has a role as a cytokine. An important role of either the intracellular or extracellular form of NAMPT has been shown in cancer, inflammation, and metabolic diseases. The first NAMPT inhibitors (FK866 and CHS828) have already entered clinical trials, and a surge in interest in the synthesis of novel molecules has occurred. The present review summarizes the recent progress in this field.
|
Noncompetitive inhibition of NAMPT (unknown origin)
|
Homo sapiens
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6279
Last Page : 6296
Authors : Galli U, Travelli C, Massarotti A, Fakhfouri G, Rahimian R, Tron GC, Genazzani AA.
Abstract : Nicotinamide phoshophoribosyltransferase (NAMPT) plays a key role in the replenishment of the NAD pool in cells. This in turn makes this enzyme an important player in bioenergetics and in the regulation of NAD-using enzymes, such as PARPs and sirtuins. Furthermore, there is now ample evidence that NAMPT is secreted and has a role as a cytokine. An important role of either the intracellular or extracellular form of NAMPT has been shown in cancer, inflammation, and metabolic diseases. The first NAMPT inhibitors (FK866 and CHS828) have already entered clinical trials, and a surge in interest in the synthesis of novel molecules has occurred. The present review summarizes the recent progress in this field.
|
Antiproliferative activity against human A2780 cells assessed as growth inhibition after 72 hrs by SRB-based microplate reader analysis
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (nampt) inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6413
Last Page : 6433
Authors : Zheng X, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Gunzner-Toste J, Liederer BM, Ly J, O'Brien T, Oh A, Wang L, Wang W, Xiao Y, Zak M, Zhao G, Yuen PW, Bair KW.
Abstract : Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.
|
Inhibition of C-terminal His-tagged NAMPT (unknown origin) expressed in Escherichia coli BL21 using nicotinamide as substrate preincubated for 15 mins before substrate addition measured after 30 mins by mass spectrometry-based assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (nampt) inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6413
Last Page : 6433
Authors : Zheng X, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Gunzner-Toste J, Liederer BM, Ly J, O'Brien T, Oh A, Wang L, Wang W, Xiao Y, Zak M, Zhao G, Yuen PW, Bair KW.
Abstract : Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.
|
Cytotoxicity against human SKOV3 cells by clonogenic assay
|
Homo sapiens
|
211.0
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human NYH cells by clonogenic assay
|
Homo sapiens
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human PC3 cells by clonogenic assay
|
Homo sapiens
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human MCF7 cells by clonogenic assay
|
Homo sapiens
|
8.4
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human A431 cells by clonogenic assay
|
Homo sapiens
|
6.1
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human A2780 cells by clonogenic assay
|
Homo sapiens
|
5.7
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Inhibition of NAMPT in human HepG2 cells using [14C]-nicotinamide/PRPP as substrate assessed as formation of [14C]-nicotinamide mononucleotide after 1 hr by liquid scintillation counting analysis
|
Homo sapiens
|
2.2
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against APO866-resistant human HCT116 cells assessed as growth inhibition after 72 hrs by WST-1 assay
|
Homo sapiens
|
946.0
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by WST-1 assay
|
Homo sapiens
|
10.9
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human MCF-7 cells assessed as growth inhibition after 72 hrs by WST-1 assay
|
Homo sapiens
|
7.4
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Cytotoxicity against human A2780 cells assessed as growth inhibition after 72 hrs by WST-1 assay
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship.
Year : 2013
Volume : 56
Issue : 22
First Page : 9071
Last Page : 9088
Authors : Christensen MK, Erichsen KD, Olesen UH, Tjørnelund J, Fristrup P, Thougaard A, Nielsen SJ, Sehested M, Jensen PB, Loza E, Kalvinsh I, Garten A, Kiess W, Björkling F.
Abstract : Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. By using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described, and the compounds are optimized. Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives, the new analogues exhibit an equally potent antiproliferative activity in vitro and comparable activity in vivo. The best performing compounds from these series showed subnanomolar antiproliferative activity toward a series of cancer cell lines (compound 15: IC50 0.025 and 0.33 nM, in A2780 (ovarian carcinoma) and MCF-7 (breast), respectively) and potent antitumor in vivo activity in well-tolerated doses in a xenograft model. In an A2780 xenograft mouse model with large tumors (500 mm(3)), compound 15 reduced the tumor volume to one-fifth of the starting volume at a dose of 3 mg/kg administered ip, bid, days 1-9. Thus, compounds found in this study compared favorably with compounds already in the clinic and warrant further investigation as promising lead molecules for the inhibition of NAMPT.
|
Antiproliferative activity against human A2780 cells after 72 hrs by sulforhodamine B assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Fragment-based identification of amides derived from trans-2-(pyridin-3-yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Year : 2014
Volume : 57
Issue : 3
First Page : 770
Last Page : 792
Authors : Giannetti AM, Zheng X, Skelton NJ, Wang W, Bravo BJ, Bair KW, Baumeister T, Cheng E, Crocker L, Feng Y, Gunzner-Toste J, Ho YC, Hua R, Liederer BM, Liu Y, Ma X, O'Brien T, Oeh J, Sampath D, Shen Y, Wang C, Wang L, Wu H, Xiao Y, Yuen PW, Zak M, Zhao G, Zhao Q, Dragovich PS.
Abstract : Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 cell culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.
|
Inhibition of C-terminal His-tagged human full-length NAMPT expressed in Escherichia coli Rosetta DE3 using nicotinamide as substrate preincubated for 15 mins followed by substrate addition measured after 30 mins in presence of PRPP
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Fragment-based identification of amides derived from trans-2-(pyridin-3-yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Year : 2014
Volume : 57
Issue : 3
First Page : 770
Last Page : 792
Authors : Giannetti AM, Zheng X, Skelton NJ, Wang W, Bravo BJ, Bair KW, Baumeister T, Cheng E, Crocker L, Feng Y, Gunzner-Toste J, Ho YC, Hua R, Liederer BM, Liu Y, Ma X, O'Brien T, Oeh J, Sampath D, Shen Y, Wang C, Wang L, Wu H, Xiao Y, Yuen PW, Zak M, Zhao G, Zhao Q, Dragovich PS.
Abstract : Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 cell culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.
|
Cytotoxicity against human SH-SY5Y cells assessed as reduction in cell viability after 48 hrs by MTT assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : MedChemComm
Title : Identification of a novel NAMPT inhibitor by combinatorial click chemistry and chemical refinement
Year : 2015
Volume : 6
Issue : 10
First Page : 1891
Last Page : 1897
Authors : Theeramunkong S, Galli U, Grolla AA, Caldarelli A, Travelli C, Massarotti A, Troiani MP, Alisi MA, Orsomando G, Genazzani AA, Tron GC
|
Inhibition of recombinant mouse NAMPT expressed in bacteria assessed as reduction in NADH formation using [14C]NAM as substrate measured for 1 hr by coupled enzymatic assay
|
Mus musculus
|
61.0
nM
|
|
Journal : MedChemComm
Title : Identification of a novel NAMPT inhibitor by combinatorial click chemistry and chemical refinement
Year : 2015
Volume : 6
Issue : 10
First Page : 1891
Last Page : 1897
Authors : Theeramunkong S, Galli U, Grolla AA, Caldarelli A, Travelli C, Massarotti A, Troiani MP, Alisi MA, Orsomando G, Genazzani AA, Tron GC
|
Inhibition of NAMPT in human SH-SY5Y cells assessed as NAD depletion incubated for 16 hrs
|
Homo sapiens
|
0.0301
nM
|
|
Journal : MedChemComm
Title : Identification of a novel NAMPT inhibitor by combinatorial click chemistry and chemical refinement
Year : 2015
Volume : 6
Issue : 10
First Page : 1891
Last Page : 1897
Authors : Theeramunkong S, Galli U, Grolla AA, Caldarelli A, Travelli C, Massarotti A, Troiani MP, Alisi MA, Orsomando G, Genazzani AA, Tron GC
|
Inhibition of human full length C-terminal His6-tagged NAMPT expressed in Escherichia coli Rosetta (DE3) cells using nicotinamide as substrate incubated for 15 mins prior to substrate addition measured after 30 mins in presence of PRPP
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.
Year : 2016
Volume : 59
Issue : 18
First Page : 8345
Last Page : 8368
Authors : Zak M, Yuen PW, Liu X, Patel S, Sampath D, Oeh J, Liederer BM, Wang W, O'Brien T, Xiao Y, Skelton N, Hua R, Sodhi J, Wang Y, Zhang L, Zhao G, Zheng X, Ho YC, Bair KW, Dragovich PS.
Abstract : NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.
|
Inhibition of NAMPT in human A2780 cells assessed as decrease in cell viability after 72 hrs by SRB assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Med Chem
Title : Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.
Year : 2016
Volume : 59
Issue : 18
First Page : 8345
Last Page : 8368
Authors : Zak M, Yuen PW, Liu X, Patel S, Sampath D, Oeh J, Liederer BM, Wang W, O'Brien T, Xiao Y, Skelton N, Hua R, Sodhi J, Wang Y, Zhang L, Zhao G, Zheng X, Ho YC, Bair KW, Dragovich PS.
Abstract : NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.
|
Inhibition of CYP3A4 in human liver microsomes using midazolam as substrate in presence of NADPH by LC-MS/MS analysis
|
Homo sapiens
|
540.0
nM
|
|
Journal : J Med Chem
Title : Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.
Year : 2016
Volume : 59
Issue : 18
First Page : 8345
Last Page : 8368
Authors : Zak M, Yuen PW, Liu X, Patel S, Sampath D, Oeh J, Liederer BM, Wang W, O'Brien T, Xiao Y, Skelton N, Hua R, Sodhi J, Wang Y, Zhang L, Zhao G, Zheng X, Ho YC, Bair KW, Dragovich PS.
Abstract : NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.
|
Inhibition of recombinant mouse NAMPT expressed in bacterial expression system using nicotinamide as substrate after 1 hr by fluorescence based NMNAT-3 enzyme coupled assay
|
Mus musculus
|
4.9
nM
|
|
Journal : J Med Chem
Title : Identification of Novel Triazole-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors Endowed with Antiproliferative and Antiinflammatory Activity.
Year : 2017
Volume : 60
Issue : 5
First Page : 1768
Last Page : 1792
Authors : Travelli C, Aprile S, Rahimian R, Grolla AA, Rogati F, Bertolotti M, Malagnino F, di Paola R, Impellizzeri D, Fusco R, Mercalli V, Massarotti A, Stortini G, Terrazzino S, Del Grosso E, Fakhfouri G, Troiani MP, Alisi MA, Grosa G, Sorba G, Canonico PL, Orsomando G, Cuzzocrea S, Genazzani AA, Galli U, Tron GC.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs. Furthermore, in the present contribution we describe the ability of 30c to significantly improve the outcome of colitis in mice. Given that this is the first report of an effect of NAMPT inhibitors in colitis, this result paves the way for novel applications for this class of compounds.
|
Cytotoxicity against human SH-SY5Y cells assessed as reduction in cell viability after 56 hrs by MTT assay
|
Homo sapiens
|
3.4
nM
|
|
Journal : J Med Chem
Title : Identification of Novel Triazole-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors Endowed with Antiproliferative and Antiinflammatory Activity.
Year : 2017
Volume : 60
Issue : 5
First Page : 1768
Last Page : 1792
Authors : Travelli C, Aprile S, Rahimian R, Grolla AA, Rogati F, Bertolotti M, Malagnino F, di Paola R, Impellizzeri D, Fusco R, Mercalli V, Massarotti A, Stortini G, Terrazzino S, Del Grosso E, Fakhfouri G, Troiani MP, Alisi MA, Grosa G, Sorba G, Canonico PL, Orsomando G, Cuzzocrea S, Genazzani AA, Galli U, Tron GC.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs. Furthermore, in the present contribution we describe the ability of 30c to significantly improve the outcome of colitis in mice. Given that this is the first report of an effect of NAMPT inhibitors in colitis, this result paves the way for novel applications for this class of compounds.
|
Cytotoxicity against human A2780 cells assessed as reduction in cell viability
|
Homo sapiens
|
4.2
nM
|
|
Journal : J Med Chem
Title : Identification of Novel Triazole-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors Endowed with Antiproliferative and Antiinflammatory Activity.
Year : 2017
Volume : 60
Issue : 5
First Page : 1768
Last Page : 1792
Authors : Travelli C, Aprile S, Rahimian R, Grolla AA, Rogati F, Bertolotti M, Malagnino F, di Paola R, Impellizzeri D, Fusco R, Mercalli V, Massarotti A, Stortini G, Terrazzino S, Del Grosso E, Fakhfouri G, Troiani MP, Alisi MA, Grosa G, Sorba G, Canonico PL, Orsomando G, Cuzzocrea S, Genazzani AA, Galli U, Tron GC.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs. Furthermore, in the present contribution we describe the ability of 30c to significantly improve the outcome of colitis in mice. Given that this is the first report of an effect of NAMPT inhibitors in colitis, this result paves the way for novel applications for this class of compounds.
|
Inhibition of human recombinant NAMPT using NAM as substrate preincubated for 5 mins followed by substrate addition measured after 15 mins by fluorescence assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : J Med Chem
Title : Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors.
Year : 2017
Volume : 60
Issue : 19
First Page : 7965
Last Page : 7983
Authors : Dong G, Chen W, Wang X, Yang X, Xu T, Wang P, Zhang W, Rao Y, Miao C, Sheng C.
Abstract : Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery.
|
Cytotoxicity in human HepG2 cells assessed as reduction in cell viability after 72 hrs by MTT assay
|
Homo sapiens
|
890.0
nM
|
|
Journal : J Med Chem
Title : Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors.
Year : 2017
Volume : 60
Issue : 19
First Page : 7965
Last Page : 7983
Authors : Dong G, Chen W, Wang X, Yang X, Xu T, Wang P, Zhang W, Rao Y, Miao C, Sheng C.
Abstract : Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery.
|
Inhibition of C-terminal His-tagged human recombinant NAMPT using FK866 or isoindoline urea-based Oregon green (488) probe incubated for 3 hrs by TR-FRET assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).
Year : 2017
Volume : 27
Issue : 15
First Page : 3317
Last Page : 3325
Authors : Curtin ML, Heyman HR, Clark RF, Sorensen BK, Doherty GA, Hansen TM, Frey RR, Sarris KA, Aguirre AL, Shrestha A, Tu N, Woller K, Pliushchev MA, Sweis RF, Cheng M, Wilsbacher JL, Kovar PJ, Guo J, Cheng D, Longenecker KL, Raich D, Korepanova AV, Soni NB, Algire MA, Richardson PL, Marin VL, Badagnani I, Vasudevan A, Buchanan FG, Maag D, Chiang GG, Tse C, Michaelides MR.
Abstract : Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
|
Antiproliferative activity against human PC3 cells assessed as reduction in cell viability incubated for 5 days by Cell-titer Glo reagent based assay
|
Homo sapiens
|
5.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).
Year : 2017
Volume : 27
Issue : 15
First Page : 3317
Last Page : 3325
Authors : Curtin ML, Heyman HR, Clark RF, Sorensen BK, Doherty GA, Hansen TM, Frey RR, Sarris KA, Aguirre AL, Shrestha A, Tu N, Woller K, Pliushchev MA, Sweis RF, Cheng M, Wilsbacher JL, Kovar PJ, Guo J, Cheng D, Longenecker KL, Raich D, Korepanova AV, Soni NB, Algire MA, Richardson PL, Marin VL, Badagnani I, Vasudevan A, Buchanan FG, Maag D, Chiang GG, Tse C, Michaelides MR.
Abstract : Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
|
Inhibition of NAMPT (unknown origin) using NAM as substrate incubated for 5 mins followed by substrate addition measured after 15 mins by fluorometric method
|
Homo sapiens
|
9.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Dual NAMPT/HDAC Inhibitors as a New Strategy for Multitargeting Antitumor Drug Discovery.
Year : 2018
Volume : 9
Issue : 1
First Page : 34
Last Page : 38
Authors : Chen W, Dong G, Wu Y, Zhang W, Miao C, Sheng C.
Abstract : Novel dual nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC) inhibitors were designed by a pharmacophore fusion approach. The thiazolocarboxamide inhibitors were highly active for both targets. In particular, compound 7f (NAMPT IC50 = 15 nM, HDAC1 IC50 = 2 nM) showed potent in vivo antitumor efficacy in the HCT116 xenograft model. The study offers a new strategy for multitarget antitumor drug discovery by simultaneously acting on cancer metabolism and epigenetics.
|
Cytotoxicity against human HepG2 cells assessed as inhibition of cell growth after 72 hrs by MTT assay
|
Homo sapiens
|
890.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Dual NAMPT/HDAC Inhibitors as a New Strategy for Multitargeting Antitumor Drug Discovery.
Year : 2018
Volume : 9
Issue : 1
First Page : 34
Last Page : 38
Authors : Chen W, Dong G, Wu Y, Zhang W, Miao C, Sheng C.
Abstract : Novel dual nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC) inhibitors were designed by a pharmacophore fusion approach. The thiazolocarboxamide inhibitors were highly active for both targets. In particular, compound 7f (NAMPT IC50 = 15 nM, HDAC1 IC50 = 2 nM) showed potent in vivo antitumor efficacy in the HCT116 xenograft model. The study offers a new strategy for multitarget antitumor drug discovery by simultaneously acting on cancer metabolism and epigenetics.
|
Inhibition of human full length C-terminal flag/His-tagged NAMPT (1 to 491 residues) expressed in HEK293-6E cells by TR-FRET assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Fragment-based discovery of a potent NAMPT inhibitor.
Year : 2018
Volume : 28
Issue : 3
First Page : 437
Last Page : 440
Authors : Korepanova A, Longenecker KL, Pratt SD, Panchal SC, Clark RF, Lake M, Gopalakrishnan SM, Raich D, Sun C, Petros AM.
Abstract : NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragment poses to that of bound FK866 we were able to synthetically elaborate one of the fragments into a potent NAMPT inhibitor.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
51.39
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Displacement of fluorescent labelled OG488 from human full length FLAG-tagged NAMPT (1 to 491 residues) expressed in HEK293-6E cells in absence of PRPP by TR-FRET assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : MedChemComm
Title : Controlling cellular distribution of drugs with permeability modifying moieties.
Year : 2019
Volume : 10
Issue : 6
First Page : 974
Last Page : 984
Authors : Richardson PL, Marin VL, Koeniger SL, Baranczak A, Wilsbacher JL, Kovar PJ, Bacon-Trusk PE, Cheng M, Hopkins TA, Haman ST, Vasudevan A.
Abstract : Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties <i>via</i> short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H<sub>3</sub>, 5HT<sub>1A</sub>, β<sub>2</sub>AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.
|
Displacement of fluorescent labelled OG488 from human full length FLAG-tagged NAMPT (1 to 491 residues) expressed in HEK293-6E cells in presence of PRPP by TR-FRET assay
|
Homo sapiens
|
0.2
nM
|
|
Journal : MedChemComm
Title : Controlling cellular distribution of drugs with permeability modifying moieties.
Year : 2019
Volume : 10
Issue : 6
First Page : 974
Last Page : 984
Authors : Richardson PL, Marin VL, Koeniger SL, Baranczak A, Wilsbacher JL, Kovar PJ, Bacon-Trusk PE, Cheng M, Hopkins TA, Haman ST, Vasudevan A.
Abstract : Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties <i>via</i> short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H<sub>3</sub>, 5HT<sub>1A</sub>, β<sub>2</sub>AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.
|
Antiproliferative activity against human PC3 cells assessed as reduction in cell viability by Celltiter-Glo assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : MedChemComm
Title : Controlling cellular distribution of drugs with permeability modifying moieties.
Year : 2019
Volume : 10
Issue : 6
First Page : 974
Last Page : 984
Authors : Richardson PL, Marin VL, Koeniger SL, Baranczak A, Wilsbacher JL, Kovar PJ, Bacon-Trusk PE, Cheng M, Hopkins TA, Haman ST, Vasudevan A.
Abstract : Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties <i>via</i> short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H<sub>3</sub>, 5HT<sub>1A</sub>, β<sub>2</sub>AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.
|
Cytotoxicity against human SH-SY5Y cells measured after 48 hrs by MTT assay
|
Homo sapiens
|
2.5
nM
|
|
Journal : Eur J Med Chem
Title : Identification of potent triazolylpyridine nicotinamide phosphoribosyltransferase (NAMPT) inhibitors bearing a 1,2,3-triazole tail group.
Year : 2019
Volume : 181
First Page : 111576
Last Page : 111576
Authors : Travelli C, Aprile S, Mattoteia D, Colombo G, Clemente N, Scanziani E, Terrazzino S, Alisi MA, Polenzani L, Grosa G, Genazzani AA, Tron GC, Galli U.
Abstract : The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC<sub>50</sub> = 5.8 nM; IC<sub>50</sub> = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports.
|
Inhibition of recombinant mouse wild-type NAMPT expressed in bacterial expression system using PRPP as substrate in presence of mouse NMNAT-3 measured for 1 hr by fluorescence assay
|
Mus musculus
|
2.7
nM
|
|
Journal : Eur J Med Chem
Title : Identification of potent triazolylpyridine nicotinamide phosphoribosyltransferase (NAMPT) inhibitors bearing a 1,2,3-triazole tail group.
Year : 2019
Volume : 181
First Page : 111576
Last Page : 111576
Authors : Travelli C, Aprile S, Mattoteia D, Colombo G, Clemente N, Scanziani E, Terrazzino S, Alisi MA, Polenzani L, Grosa G, Genazzani AA, Tron GC, Galli U.
Abstract : The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC<sub>50</sub> = 5.8 nM; IC<sub>50</sub> = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports.
|
Inhibition of recombinant NAMPT (unknown origin) using NAM and PRPP as substrates incubated for 60 mins in presence of NMNAT1 measured at 5 mins interval for 30 mins by WST1 assay
|
Homo sapiens
|
6.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.
Year : 2019
Volume : 29
Issue : 12
First Page : 1502
Last Page : 1506
Authors : Zhang K, Ni Y, Chen J, Tu Z, Wu X, Chen D, Yao H, Jiang S.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC<sub>50</sub> = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC<sub>50</sub> values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC<sub>50</sub> values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
|
Antiproliferative activity against human K562 cells assessed as inhibition of cell growth after 72 hrs by CCK-8 assay
|
Homo sapiens
|
0.96
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.
Year : 2019
Volume : 29
Issue : 12
First Page : 1502
Last Page : 1506
Authors : Zhang K, Ni Y, Chen J, Tu Z, Wu X, Chen D, Yao H, Jiang S.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC<sub>50</sub> = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC<sub>50</sub> values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC<sub>50</sub> values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
|
Antiproliferative activity against human MCF7 cells assessed as inhibition of cell growth after 72 hrs by CCK-8 assay
|
Homo sapiens
|
0.41
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.
Year : 2019
Volume : 29
Issue : 12
First Page : 1502
Last Page : 1506
Authors : Zhang K, Ni Y, Chen J, Tu Z, Wu X, Chen D, Yao H, Jiang S.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC<sub>50</sub> = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC<sub>50</sub> values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC<sub>50</sub> values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
|
Antiproliferative activity against human DU145 cells assessed as inhibition of cell growth after 72 hrs by CCK-8 assay
|
Homo sapiens
|
5.12
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.
Year : 2019
Volume : 29
Issue : 12
First Page : 1502
Last Page : 1506
Authors : Zhang K, Ni Y, Chen J, Tu Z, Wu X, Chen D, Yao H, Jiang S.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC<sub>50</sub> = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC<sub>50</sub> values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC<sub>50</sub> values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
|
Antiproliferative activity against human HeLa cells assessed as inhibition of cell growth after 72 hrs by CCK-8 assay
|
Homo sapiens
|
3.75
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.
Year : 2019
Volume : 29
Issue : 12
First Page : 1502
Last Page : 1506
Authors : Zhang K, Ni Y, Chen J, Tu Z, Wu X, Chen D, Yao H, Jiang S.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC<sub>50</sub> = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC<sub>50</sub> values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC<sub>50</sub> values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
|
Antiproliferative activity against human NCI-H1975 cells harboring EGFR L858R/T790M mutation assessed as inhibition of cell growth after 72 hrs by CCK-8 assay
|
Homo sapiens
|
4.76
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.
Year : 2019
Volume : 29
Issue : 12
First Page : 1502
Last Page : 1506
Authors : Zhang K, Ni Y, Chen J, Tu Z, Wu X, Chen D, Yao H, Jiang S.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC<sub>50</sub> = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC<sub>50</sub> values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC<sub>50</sub> values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
|
Antiproliferative activity against human HuH7 cells assessed as inhibition of cell growth after 72 hrs by CCK-8 assay
|
Homo sapiens
|
1.05
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of trans-3-(pyridin-3-yl)acrylamide-derived sulfamides as potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for the potential treatment of cancer.
Year : 2019
Volume : 29
Issue : 12
First Page : 1502
Last Page : 1506
Authors : Zhang K, Ni Y, Chen J, Tu Z, Wu X, Chen D, Yao H, Jiang S.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC<sub>50</sub> = 5.08 nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC<sub>50</sub> values of 2.90 nM, 2.34 nM, and 2.24 nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC<sub>50</sub> values of 0.46 nM, 0.23 nM and 0.53 nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
|
Inhibition of recombinant NAMPT (unknown origin) using nicotinamide as substrate measured every 5 mins for 30 mins in presence of recombinant NMNAT1
|
Homo sapiens
|
32.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design of Potent Nicotinamide Phosphoribosyltransferase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities.
Year : 2016
Volume : 59
Issue : 12
First Page : 5766
Last Page : 5779
Authors : Bai J, Liao C, Liu Y, Qin X, Chen J, Qiu Y, Qin D, Li Z, Tu ZC, Jiang S.
Abstract : Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) has the potential to directly limit NAD production in cancer cells and is an effective strategy for cancer treatment. Using a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of NAMPT. Several designed compounds showed promising antiproliferative activities in vitro. (E)-N-(5-((4-(((2-(1H-Indol-3-yl)ethyl)(isopropyl)amino)methyl)phenyl)amino)pentyl)-3-(pyridin-3-yl)acrylamide, 30, bearing an indole moiety, has an IC50 of 25.3 nM for binding to the NAMPT protein and demonstrated promising inhibitory activities in the nanomolar range against several cancer cell lines (MCF-7 GI50 = 0.13 nM; MDA-MB-231 GI50 = 0.15 nM). Triple-negative breast cancer is the most malignant subtype of breast cancer with no effective targeted treatments currently available. Significant antitumor efficacy of compound 30 was achieved (TGI was 73.8%) in an orthotopic MDA-MB-231 triple-negative breast cancer xenograft tumor model. This paper reports promising lead molecules for the inhibition of NAMPT which could serve as a basis for further investigation.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.05
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.05
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.19
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.59
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.19
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.59
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Cytotoxicity against human HepG2 cells assessed as reduction in cell viability measured after 72 hrs by SRB assay
|
Homo sapiens
|
18.72
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of small-molecule urea derivatives as novel NAMPT inhibitors via pharmacophore-based virtual screening.
Year : 2020
Volume : 28
Issue : 1
First Page : 115217
Last Page : 115217
Authors : Ozgencil F, Eren G, Ozkan Y, Guntekin-Ergun S, Cetin-Atalay R.
Abstract : Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-prophosphate (PRPP) to yield nicotinamide mononucleotide (NMN), a rate limiting enzyme in a mammalian salvage pathway of nicotinamide adenine dinucleotide (NAD<sup>+</sup>) synthesis. Recently, intracellular NAD<sup>+</sup> has received substantial attention due to the recent discovery that several enzymes including poly(ADP-ribose) polymerases (PARPs), mono(ADP-ribose) transferases (ARTs), and sirtuins (SIRTs), use NAD<sup>+</sup> as a substrate, suggesting that intracellular NAD<sup>+</sup> level may regulate cytokine production, metabolism, and aging through these enzymes. NAMPT is found to be upregulated in various types of cancer, and given its importance in the NAD<sup>+</sup> salvage pathway, NAMPT is considered as an attractive target for the development of new cancer therapies. In this study, the reported NAMPT inhibitors bearing amide, cyanoguanidine, and urea scaffolds were used to generate pharmacophore models and pharmacophore-based virtual screening studies were performed against ZINC database. Following the filtering steps, ten hits were identified and evaluated for their in vitro NAMPT inhibitory effects. Compounds GF4 (NAMPT IC<sub>50</sub> = 2.15 ± 0.22 μM) and GF8 (NAMPT IC<sub>50</sub> = 7.31 ± 1.59 μM) were identified as new urea-typed inhibitors of NAMPT which also displayed cytotoxic activities against human HepG2 hepatocellular carcinoma cell line with IC<sub>50</sub> values of 15.20 ± 1.28 and 24.28 ± 6.74 μM, respectively.
|
Inhibition of recombinant NAMPT (unknown origin) using nicotinamide and pyrophosphate as substrate incubated for 60 mins and measured for 30 mins at 5 mins interval by colorimetric assay
|
Homo sapiens
|
20.7
nM
|
|
