|
Binding affinity to Bcl-2 (unknown origin) by FRET assay
|
Homo sapiens
|
0.01
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on-target toxicity.
Year : 2016
Volume : 26
Issue : 9
First Page : 2105
Last Page : 2114
Authors : Hennessy EJ.
Abstract : The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. Accordingly, compounds that interact with the Bcl-2 family of proteins, which are critical regulators of the apoptotic process, have been widely pursued as potential anticancer agents. While encouraging antitumor activity in clinical trials has been observed with some of these compounds, their therapeutic utility is often limited by accompanying toxicities associated with the interaction with this family of proteins. As a result, there has been recent interest in identifying agents that can selectively target a single Bcl-2 family member (such as Bcl-2 or Bcl-xL), with the expectation that improved therapeutic margins can be achieved. In this review, we outline the biological rationale behind this approach, and highlight key examples of selective compounds from the recent literature alongside the structural basis for the reported selectivity.
|
Binding affinity to Bcl-XL (unknown origin) by FRET assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on-target toxicity.
Year : 2016
Volume : 26
Issue : 9
First Page : 2105
Last Page : 2114
Authors : Hennessy EJ.
Abstract : The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. Accordingly, compounds that interact with the Bcl-2 family of proteins, which are critical regulators of the apoptotic process, have been widely pursued as potential anticancer agents. While encouraging antitumor activity in clinical trials has been observed with some of these compounds, their therapeutic utility is often limited by accompanying toxicities associated with the interaction with this family of proteins. As a result, there has been recent interest in identifying agents that can selectively target a single Bcl-2 family member (such as Bcl-2 or Bcl-xL), with the expectation that improved therapeutic margins can be achieved. In this review, we outline the biological rationale behind this approach, and highlight key examples of selective compounds from the recent literature alongside the structural basis for the reported selectivity.
|
Binding affinity to His-tagged Bcl-XL (unknown origin) incubated for 30 mins by TR-FRET assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting Mcl-1: the search for a silver bullet in cancer therapy
Year : 2016
Volume : 7
Issue : 5
First Page : 778
Last Page : 787
Authors : Nhu D, Lessene G, Huang DCS, Burns CJ
|
Binding affinity to BCL2 (unknown origin) incubated for 30 mins by TR-FRET assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting Mcl-1: the search for a silver bullet in cancer therapy
Year : 2016
Volume : 7
Issue : 5
First Page : 778
Last Page : 787
Authors : Nhu D, Lessene G, Huang DCS, Burns CJ
|
Binding affinity to MCL1 (unknown origin) incubated for 30 mins by TR-FRET assay
|
Homo sapiens
|
444.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting Mcl-1: the search for a silver bullet in cancer therapy
Year : 2016
Volume : 7
Issue : 5
First Page : 778
Last Page : 787
Authors : Nhu D, Lessene G, Huang DCS, Burns CJ
|
Inhibition of FAM-Bid binding to human MCL1 expressed in Escherichia coli BL21 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
780.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins.
Year : 2016
Volume : 7
Issue : 12
First Page : 1185
Last Page : 1190
Authors : Lu Y, Wu S, Yue Y, He S, Li J, Tang J, Wang W, Zhou HB.
Abstract : A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins.
|
Inhibition of FAM-Bid binding to human BCL2 expressed in Escherichia coli BL21 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
Inhibition of FAM-Bid binding to human BCL2 expressed in Escherichia coli BL21 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins.
Year : 2016
Volume : 7
Issue : 12
First Page : 1185
Last Page : 1190
Authors : Lu Y, Wu S, Yue Y, He S, Li J, Tang J, Wang W, Zhou HB.
Abstract : A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins.
|
Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay: The inhibition constant (Ki) is the dissociation constant of an enzyme-inhibitor complex or a protein/small molecule complex, wherein the small molecule is inhibiting binding of one protein to another protein or peptide. Where the Ki for a compound is represented as > (greater than) a certain numerical value, it is intended to mean that the binding affinity value (e.g., for Bcl-XL) is greater than the limits of detection of the assay used. Where the binding selectivity ratio for a compound is represented as > (greater than) a certain numerical value, it is intended to mean that the selectivity of a particular compound for Bcl-2 over Bcl-XL is at least as great as the number indicated. Where the Ki for a compound is represented as < (less than) a certain numerical value, it is intended to mean that the binding affinity value (e.g., for Bcl-2) is lower than the limit of detection of the assay used. Inhibition constants were determined using Wang's equation (Wang Z-X).
|
Homo sapiens
|
0.036
nM
|
|
Title : Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases
Year : 2015
|
Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay: Representative compounds were serially diluted in dimethyl sulfoxide (DMSO) starting at 50 uM (2x starting concentration; 10% DMSO) and 10 uL were transferred into a 384-well plate. Then 10 uL of a protein/probe/antibody mix was added to each well at final concentrations listed in TABLE 1. Protein:GST-Bcl-2, Probe: F-Bak Peptide Probe Acetyl-GQVGRQLAIIGDK(6-FAM)INR-amide(SEQ ID NO: 1), Protein(nM): 1, Probe (nM): 100, Antibody: Tb-anit-GST, Antibody (nm): 1. The samples are then mixed on a shaker for 1 minute and incubated for an additional 3 hours at room temperature. For each assay, the probe/antibody and protein/probe/antibody were included on each assay plate as negative and positive controls, respectively. Fluorescence was measured on the ENVISION plate reader (Perkin Elmer) using a 340/35 nm excitation filter and 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeled anti-Histidine antibody) emission filters.
|
Homo sapiens
|
0.01
nM
|
|
Title : Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
Year : 2015
|
Binding affinity to Bcl-2 (unknown origin) by TR-FRET assay
|
Homo sapiens
|
0.01
nM
|
|
Journal : J Med Chem
Title : Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules.
Year : 2017
Volume : 60
Issue : 3
First Page : 821
Last Page : 838
Authors : Yap JL, Chen L, Lanning ME, Fletcher S.
Abstract : A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.
|
Binding affinity to Bcl-xL (unknown origin) by TR-FRET assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : J Med Chem
Title : Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules.
Year : 2017
Volume : 60
Issue : 3
First Page : 821
Last Page : 838
Authors : Yap JL, Chen L, Lanning ME, Fletcher S.
Abstract : A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.
|
Binding affinity to Bcl-w (unknown origin) by TR-FRET assay
|
Homo sapiens
|
245.0
nM
|
|
Journal : J Med Chem
Title : Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules.
Year : 2017
Volume : 60
Issue : 3
First Page : 821
Last Page : 838
Authors : Yap JL, Chen L, Lanning ME, Fletcher S.
Abstract : A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.
|
Binding affinity to Mcl-1 (unknown origin) by TR-FRET assay
|
Homo sapiens
|
444.0
nM
|
|
Journal : J Med Chem
Title : Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules.
Year : 2017
Volume : 60
Issue : 3
First Page : 821
Last Page : 838
Authors : Yap JL, Chen L, Lanning ME, Fletcher S.
Abstract : A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.
|
Cytotoxicity against human RS4:11 cells assessed as reduction in cell viability
|
Homo sapiens
|
1.5
nM
|
|
Journal : Eur J Med Chem
Title : Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents.
Year : 2018
Volume : 146
First Page : 471
Last Page : 482
Authors : Wan Y, Dai N, Tang Z, Fang H.
Abstract : The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.
|
Inhibition of Bcl-2 (unknown origin) by TR-FRET assay
|
Homo sapiens
|
0.01
nM
|
|
Journal : Eur J Med Chem
Title : Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents.
Year : 2018
Volume : 146
First Page : 471
Last Page : 482
Authors : Wan Y, Dai N, Tang Z, Fang H.
Abstract : The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.
|
Inhibition of Bcl-xL (unknown origin) by TR-FRET assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : Eur J Med Chem
Title : Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents.
Year : 2018
Volume : 146
First Page : 471
Last Page : 482
Authors : Wan Y, Dai N, Tang Z, Fang H.
Abstract : The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.
|
Inhibition of Mcl-1 (unknown origin) by TR-FRET assay
|
Homo sapiens
|
444.0
nM
|
|
Journal : Eur J Med Chem
Title : Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents.
Year : 2018
Volume : 146
First Page : 471
Last Page : 482
Authors : Wan Y, Dai N, Tang Z, Fang H.
Abstract : The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.
|
Cytotoxicity against human RS4:11 cells assessed as reduction in cell viability after 24 hrs by MTT assay
|
Homo sapiens
|
330.0
nM
|
|
Journal : Eur J Med Chem
Title : Dual inhibitors of the pro-survival proteins Bcl-2 and Mcl-1 derived from natural compound meiogynin A.
Year : 2018
Volume : 148
First Page : 26
Last Page : 38
Authors : Abou Samra A, Robert A, Gov C, Favre L, Eloy L, Jacquet E, Bignon J, Wiels J, Desrat S, Roussi F.
Abstract : Thirty analogues of natural meiogynin A, a pan-Bcl-2 inhibitor, were prepared in order to elaborate cytotoxic compounds on specific cancer cells overexpressing one or more proteins of the Bcl-2 family. The interaction of all the new analogues with Bcl-xL, Mcl-1 and Bcl-2 proteins was first evaluated by fluorescence polarization assay (FPA) and showed that modulation of the lateral chain has a dramatic impact as subtle changes significantly modify the activity on the target proteins. The acetoxymethyl prodrugs of the two most active compounds were then elaborated to determine their cytotoxicity on B cell lines. A strong cytotoxic effect on BL2, RS4;11 and H929 cells was observed with a triazole prodrug that induces apoptosis.
|
Displacement of Bax-derived peptide from Bcl-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
7.39
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors.
Year : 2018
Volume : 26
Issue : 2
First Page : 443
Last Page : 454
Authors : Liu X, Zhang Y, Huang W, Tan W, Zhang A.
Abstract : The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.
|
Displacement of Bad-derived peptide from Bcl-XL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
52.7
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors.
Year : 2018
Volume : 26
Issue : 2
First Page : 443
Last Page : 454
Authors : Liu X, Zhang Y, Huang W, Tan W, Zhang A.
Abstract : The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.
|
Inhibition of Bcl2 (unknown origin)
|
Homo sapiens
|
0.01
nM
|
|
Journal : J Med Chem
Title : Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations.
Year : 2018
Volume : 61
Issue : 15
First Page : 6421
Last Page : 6467
Authors : Young RJ, Leeson PD.
Abstract : The practices and tactics employed in successful optimizations are examined, judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technology) and types of molecules, including those beyond the rule of five. The wider employment of efficiency metrics and lipophilicity control is evident in contemporary practice and the impact on quality demonstrable. What is clear is that while targets are different, successful molecules are almost invariably among the most efficient for their target, even at the extremes. Trajectory mapping, based on principles rather than rules, is useful in assessing quality and progress in optimizations while benchmarking against competitors and assessing property-dependent risks.
|
Inhibition of Bcl2 (unknown origin)
|
Homo sapiens
|
0.01
nM
|
|
Journal : J Med Chem
Title : Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection.
Year : 2018
Volume : 61
Issue : 7
First Page : 2636
Last Page : 2651
Authors : DeGoey DA, Chen HJ, Cox PB, Wendt MD.
Abstract : Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
|
Inhibition of Bcl-xL (unknown origin)
|
Homo sapiens
|
48.0
nM
|
|
Journal : J Med Chem
Title : Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection.
Year : 2018
Volume : 61
Issue : 7
First Page : 2636
Last Page : 2651
Authors : DeGoey DA, Chen HJ, Cox PB, Wendt MD.
Abstract : Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
|
Antiproliferative activity against human RS4:11 cells in presence of 10% human serum
|
Homo sapiens
|
8.0
nM
|
|
Journal : J Med Chem
Title : Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection.
Year : 2018
Volume : 61
Issue : 7
First Page : 2636
Last Page : 2651
Authors : DeGoey DA, Chen HJ, Cox PB, Wendt MD.
Abstract : Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
|
Inhibition of FAM-labelled Bax binding to Bcl2 (unknown origin) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
7.4
nM
|
|
Journal : Eur J Med Chem
Title : Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin.
Year : 2018
Volume : 159
First Page : 149
Last Page : 165
Authors : Liu X, Zhang Y, Huang W, Luo J, Li Y, Tan W, Zhang A.
Abstract : By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax.
|
Inhibition of FAM-labelled Bax binding to Bcl-xL (unknown origin) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
52.7
nM
|
|
Journal : Eur J Med Chem
Title : Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin.
Year : 2018
Volume : 159
First Page : 149
Last Page : 165
Authors : Liu X, Zhang Y, Huang W, Luo J, Li Y, Tan W, Zhang A.
Abstract : By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax.
|
Antiproliferative activity against human RS4:11 cells after 72 hrs by MTS assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin.
Year : 2018
Volume : 159
First Page : 149
Last Page : 165
Authors : Liu X, Zhang Y, Huang W, Luo J, Li Y, Tan W, Zhang A.
Abstract : By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax.
|
Antiproliferative activity against human Toledo cells after 72 hrs by MTS assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : Eur J Med Chem
Title : Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin.
Year : 2018
Volume : 159
First Page : 149
Last Page : 165
Authors : Liu X, Zhang Y, Huang W, Luo J, Li Y, Tan W, Zhang A.
Abstract : By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax.
|
Inhibition of FAM-Bid peptide binding to Bcl2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
230.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma.
Year : 2019
Volume : 29
Issue : 3
First Page : 349
Last Page : 352
Authors : Zhou R, Fang S, Zhang M, Zhang Q, Hu J, Wang M, Wang C, Zhu J, Shen A, Chen X, Zheng C.
Abstract : Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e-7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
|
Inhibition of BCL-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Eur J Med Chem
Title : Clinical candidates modulating protein-protein interactions: The fragment-based experience.
Year : 2019
Volume : 167
First Page : 76
Last Page : 95
Authors : Valenti D, Hristeva S, Tzalis D, Ottmann C.
Abstract : Protein-protein interactions (PPIs) cover a very wide range of biological functions and consequently have become one of the favourite targets for new therapeutic strategies. PPIs are strongly characterised by an intricate and dynamic network of surface interactions occurring between two or more proteins. Because of the complexity of these interactions, many strategies have been applied with the aim to find selective modulators for a specific protein-protein complex. During the last decade, fragment-based approaches have served many drug discovery programs with an impressive increment of contributions, gaining a remarkable role in PPIs modulators' development. In this review, we detail the successful fragment-to-clinical candidate evolutions related to PPI modulation. An overview on the physico-chemical properties of both fragment hits and lead compounds will be presented together with a statistical analysis of their distribution.
|
Inhibition of wild-type BCL-2 (unknown origin) expressed in Escherichia coli BL21 cells using biotinylated BIMBH3 or BAXBH3 peptide by surface plasmon resonance assay
|
Homo sapiens
|
0.018
nM
|
|
Journal : J Med Chem
Title : Hot-Spots of Mcl-1 Protein.
Year : 2020
Volume : 63
Issue : 3
First Page : 928
Last Page : 943
Authors : Denis C, Sopková-de Oliveira Santos J, Bureau R, Voisin-Chiret AS.
Abstract : Protein-protein interactions (PPIs) control many important physiological processes within human cells. Apoptosis or programmed cell death is closely regulated by pro- and antiapoptotic signals. Dysregulation of this homeostasis is implicated in tumorigenesis and acquired resistance to treatments. The emerging importance of Mcl-1 protein in chemotherapeutic resistance makes it a high priority therapeutic target. Targeting PPIs associated with Mcl-1 presents many challenges for the design of inhibitors. This review focuses on the characterization of the Mcl-1 hot-spots which are related to four hydrophobic pockets P1-P4 and one major electrostatic interaction. Analysis of structural data highlights the high importance of the P2/P3 pockets for the binding of nonpeptide ligands. In order to guide medicinal chemists into making more selective and potent Mcl-1 inhibitors, the Mcl-1 protein is compared to other antiapoptotic proteins.
|
Inhibition of Bcl2 (unknown origin)
|
Homo sapiens
|
0.01
nM
|
|
Journal : Eur J Med Chem
Title : The chemical biology of apoptosis: Revisited after 17 years.
Year : 2019
Volume : 177
First Page : 63
Last Page : 75
Authors : Yang S, Mao Y, Zhang H, Xu Y, An J, Huang Z.
Abstract : A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
18.84
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
21.72
%
|
|
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
|
-0.32
%
|
|
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
|
-0.29
%
|
|
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
|
-0.32
%
|
|
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
|
-0.29
%
|
|
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.
|
Inhibition of BCL2 (unknown origin) by TR-FRET assay
|
Homo sapiens
|
0.01
nM
|
|
Journal : J Med Chem
Title : Fragment Linking Strategies for Structure-Based Drug Design.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11420
Last Page : 11435
Authors : Bancet A,Raingeval C,Lomberget T,Le Borgne M,Guichou JF,Krimm I
Abstract : Fragment-based drug discovery is a strategy widely used in both academia and pharmaceutical companies to generate small-molecule protein inhibitors and drug candidates. Among the approaches reported in the literature (growing, linking, and merging), the linking approach theoretically offers the opportunity to rapidly gain in binding energy. Nevertheless, this approach is poorly represented when considering the compounds currently in clinical trials. Here, we report an exhaustive view of the cases published so far in the literature, together with the methods used to identify the two initial fragments either simultaneously or successively. We review the different types of linkers published and discuss how these linkers are designed to obtain the lead compound. Mixing merging and linking methods, where the linker is duplicated from a known inhibitor, appears as an interesting strategy. To reach superadditivity, we propose to grow one of the fragments in order to minimize the distance between the two binders and then link the resulting compounds using flexible alkyl-derived linkers.
|
Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) at 20uM using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
97.2
%
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Binding affinity to human full-length N-terminal His6-tagged Bcl2 (2 to 206 residues) expressed in Escherichia coli S12 extract by isothermal titration calorimetry
|
Homo sapiens
|
3.1
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Binding affinity to human full-length N-terminal His6-tagged prephosphorylated Bcl2 (2 to 206 residues) expressed in Escherichia coli S12 extract by isothermal titration calorimetry
|
Homo sapiens
|
705.0
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Binding affinity to human full-length N-terminal His6-tagged Bcl2 R106A/R109A mutant expressed in Escherichia coli S12 extract by isothermal titration calorimetry
|
Homo sapiens
|
4.5
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Binding affinity to human full-length N-terminal His6-tagged prephosphorylated Bcl2 R106A/R109A mutant expressed in Escherichia coli S12 extract by isothermal titration calorimetry
|
Homo sapiens
|
5.5
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Induction of apoptosis in human KG-1 cells measured after 48 hrs by FITC-Annexin V/PS staining based
|
Homo sapiens
|
850.0
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Binding affinity to Bc1-xL (unknown origin) by fluorescence polarization competition assay
|
Homo sapiens
|
1.0
nM
|
|
|
Displacement of Bak derived peptide from Bcl-2 (unknown origin) measured after 15 mins by microplate reader assay
|
Homo sapiens
|
1.0
nM
|
|
|
Displacement of Bak derived peptide from Bcl-xL (unknown origin) measured after 15 mins by microplate reader assay
|
Homo sapiens
|
157.0
nM
|
|
|
Antiproliferative activity against human RS4-11 cells assessed as inhibition of cell proliferation measured after 72 hrs by CCK8 assay
|
Homo sapiens
|
1.8
nM
|
|
|
Inhibition of FAM-Bim peptide binding to human Bcl-2 (2 to 206) measured after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
100.0
nM
|
|
|
Binding affinity to full length human Bcl-xl expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant preincubated for 30 mins followed by 5-FAM-QEDIIIINIARHLAQVGDSMD-RSIPPG tracer addition and measured after 20 mins by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
|
Binding affinity to full length human Bcl-2 expressed in Escherichia coli BL21 (DE3) assessed as inhibition constant preincubated for 30 mins followed by 5-FAM-QEDIIIINIARHLAQVGDSMD-RSIPPG tracer addition and measured after 20 mins by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
|
Cytotoxicity against human HL-60 cells assessed as inhibition of cell growth incubated for 48 hrs by CCK8 assay
|
Homo sapiens
|
77.0
nM
|
|
|
Cytotoxicity against human RS4-11 cells assessed as inhibition of cell growth incubated for 48 hrs by CCK8 assay
|
Homo sapiens
|
4.3
nM
|
|
