BMS-214662


Synonyms	Bms 214662 Bms-214662
Status
Molecule Category	UNKNOWN
UNII	L2U9GFD244
EPA CompTox	DTXSID20173260


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	OLCWFLWEHWLBTO-HSZRJFAPSA-N
Smiles	N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
InChI	InChI=1S/C25H23N5O2S2/c26-13-20-8-9-24-21(11-20)15-30(34(31,32)25-7-4-10-33-25)23(12-19-5-2-1-3-6-19)17-29(24)16-22-14-27-18-28-22/h1-11,14,18,23H,12,15-17H2,(H,27,28)/t23-/m1/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C25H23N5O2S2
Molecular Weight	489.63
AlogP	4.17
Hydrogen Bond Acceptor	6.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	6.0
Polar Surface Area	93.09
Molecular species	NEUTRAL
Aromatic Rings	4.0
Heavy Atoms	34.0

Reference

Journal : J. Med. Chem.

Title : Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors.

PubMed ID : 14736242

DOI : 10.1021/jm030434f

Year : 2004

Volume : 47

Issue : 3

First Page : 612

Last Page : 626

Authors : Wang L, Wang GT, Wang X, Tong Y, Sullivan G, Park D, Leonard NM, Li Q, Cohen J, Gu WZ, Zhang H, Bauch JL, Jakob CG, Hutchins CW, Stoll VS, Marsh K, Rosenberg SH, Sham HL, Lin NH.

Abstract : A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Synthesis of N,N'-disubstituted 3-aminobenzo[c] and [d]azepin-2-ones as potent and specific farnesyl transferase inhibitors.

PubMed ID : 14741286

DOI : 10.1016/j.bmcl.2003.11.013

Year : 2004

Volume : 14

Issue : 3

First Page : 767

Last Page : 771

Authors : Le Diguarher T, Ortuno JC, Shanks D, Guilbaud N, Pierré A, Raimbaud E, Fauchère JL, Hickman JA, Tucker GC, Casara PJ.

Abstract : A structure-activity study was performed by synthesis on N,N'-disubstitution of 3-aminobenzo[c] and [d]azepin-2-one 2 and 3 to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities.

Reference

Journal : J. Med. Chem.

Title : Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity.

PubMed ID : 11020273

DOI : 10.1021/jm000248z

Year : 2000

Volume : 43

Issue : 20

First Page : 3587

Last Page : 3595

Authors : Hunt JT, Ding CZ, Batorsky R, Bednarz M, Bhide R, Cho Y, Chong S, Chao S, Gullo-Brown J, Guo P, Kim SH, Lee FY, Leftheris K, Miller A, Mitt T, Patel M, Penhallow BA, Ricca C, Rose WC, Schmidt R, Slusarchyk WA, Vite G, Manne V.

Abstract : Continuing structure-activity studies were performed on the 2,3,4, 5-tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepine farnesyltransferase (FT) inhibitors. These studies demonstrated that a 3(R)-phenylmethyl group, a hydrophilic 7-cyano group, and a 4-sulfonyl group bearing a variety of substituents provide low-nanomolar FT inhibitors with cellular activity at concentrations below 100 nM. Maximal in vivo activity in the mutated K-Ras bearing HCT-116 human colon tumor model was achieved with analogues carrying hydrophobic side chains such as propyl, phenyl, or thienyl attached to the N-4 sulfonyl group. Several such compounds achieved curative efficacy when given orally in this model. On the basis of its excellent preclinical antitumor activity and promising pharmacokinetics, compound 20 (BMS-214662, (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thie nyl sulfonyl)-1H-1,4-benzodiazepine) has been advanced into human clinical trials.

Reference

Journal : J. Med. Chem.

Title : Inhibitors of farnesyltransferase: a rational approach to cancer chemotherapy?

PubMed ID : 15055985

DOI : 10.1021/jm0305467

Year : 2004

Volume : 47

Issue : 8

First Page : 1869

Last Page : 1878

Authors : Bell IM.

Reference

Journal : J. Med. Chem.

PubMed ID : 11020273

DOI : 10.1021/jm000248z

Year : 2000

Volume : 43

Issue : 20

First Page : 3587

Last Page : 3595

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Synthesis of N,N'-disubstituted 3-aminobenzo[c] and [d]azepin-2-ones as potent and specific farnesyl transferase inhibitors.

PubMed ID : 14741286

DOI : 10.1016/j.bmcl.2003.11.013

Year : 2004

Volume : 14

Issue : 3

First Page : 767

Last Page : 771

Authors : Le Diguarher T, Ortuno JC, Shanks D, Guilbaud N, Pierré A, Raimbaud E, Fauchère JL, Hickman JA, Tucker GC, Casara PJ.

Reference

Journal : J. Med. Chem.

Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.

PubMed ID : 20925433

DOI : 10.1021/jm100189a

Year : 2010

Volume : 53

Issue : 19

First Page : 6779

Last Page : 6810

Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.

Reference

Journal : J. Med. Chem.

Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.

PubMed ID : 20925433

DOI : 10.1021/jm100189a

Year : 2010

Volume : 53

Issue : 19

First Page : 6779

Last Page : 6810

Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Synthesis and biological evaluation of new phenothiazine derivatives bearing a pyrazole unit as protein farnesyltransferase inhibitors.

PubMed ID : 23036952

DOI : 10.1016/j.bmcl.2012.09.030

Year : 2012

Volume : 22

Issue : 22

First Page : 6896

Last Page : 6902

Authors : Baciu-Atudosie L, Ghinet A, Farce A, Dubois J, Belei D, Bîcu E.

Abstract : A new family of protein farnesyltransferase inhibitors, based on a phenothiazine scaffold, was designed and synthesized. The biological evaluation of these products showed that compounds 28 and 30 were the most active, with protein farnesyltransferase inhibition potencies in the low micromolar range. Compounds were also evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. Indenopyrazole 30 exhibited the most potent in vitro cytostatic activity inhibiting the growth of HCT-116, LOX IMVI and SK-MEL-5 cell lines.

Reference

Journal : J. Med. Chem.

Title : Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators.

PubMed ID : 23566315

DOI : 10.1021/jm3017706

Year : 2013

Volume : 56

Issue : 13

First Page : 5219

Last Page : 5230

Authors : Wang Y, Kaiser CE, Frett B, Li HY.

Abstract : The RAS proteins play a role in cell differentiation, proliferation, and survival. Aberrant RAS signaling has been found to play a role in 30% of all cancers. KRAS, a key member of the RAS protein family, is an attractive cancer target, as frequent point mutations in the KRAS gene render the protein constitutively active. A number of attempts have been made to target aberrant KRAS signaling by identifying small molecule compounds that (1) are synthetic lethal to mutant KRAS, (2) block KRAS/GEF interactions, (3) inhibit downstream KRAS effectors, or (4) inhibit the post-translational processing of RAS proteins. In addition, inhibition of novel targets outside the main KRAS signaling pathway, specifically the cell cycle related kinase PLK1, has been shown have an effect in cells that harbor mutant KRAS. Herein we review the use of various high-throughput screening assays utilized to identify new small-molecule compounds capable of targeting mutant KRAS-driven cancers.

Reference

Journal : J. Med. Chem.

Title : Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators.

PubMed ID : 23566315

DOI : 10.1021/jm3017706

Year : 2013

Volume : 56

Issue : 13

First Page : 5219

Last Page : 5230

Authors : Wang Y, Kaiser CE, Frett B, Li HY.

Reference

Journal : J Med Chem

Title : Interrogating the Roles of Post-Translational Modifications of Non-Histone Proteins.

PubMed ID : 28505447

DOI : 10.1021/acs.jmedchem.6b01817

Year : 2018

Volume : 61

Issue : 8

First Page : 3239

Last Page : 3252

Authors : Buuh ZY, Lyu Z, Wang RE.

Abstract : Post-translational modifications (PTMs) allot versatility to the biological functions of highly conserved proteins. Recently, modifications to non-histone proteins such as methylation, acetylation, phosphorylation, glycosylation, ubiquitination, and many more have been linked to the regulation of pivotal pathways related to cellular response and stability. Due to the roles these dynamic modifications assume, their dysregulation has been associated with cancer and many other important diseases such as inflammatory disorders and neurodegenerative diseases. For this reason, we present a review and perspective on important post-translational modifications on non-histone proteins, with emphasis on their roles in diseases and small molecule inhibitors developed to target PTM writers. Certain PTMs' contribution to epigenetics has been extensively expounded; yet more efforts will be needed to systematically dissect their roles on non-histone proteins, especially for their relationships with nononcological diseases. Finally, current research approaches for PTM study will be discussed and compared, including limitations and possible improvements.

Assay Description	Organism	Bioactivity
Inhibition of Farnesyltransferase	None	0.7 nM
Inhibition of farnesyltransferase	None	1.3 nM
Inhibition of purified recombinant human farnesyltransferase (FT)	None	1.35 nM
Inhibitory concentration against farnesyltransferase was determined	Homo sapiens	1.4 nM
Inhibition of anchorage independent growth of H-ras transformed NIH3T3 cells in Soft Agar	Mus musculus	25.0 nM
Inhibitory activity against v-H-Ras gene transfected cell line	None	25.0 nM
Inhibition of FTase	None	1.35 nM
Inhibition of FTase in mouse NIH3T3 cells	Mus musculus	25.0 nM
Inhibition of human FTase	Homo sapiens	1.4 nM
Inhibition of farnesyltransferase (unknown origin) assessed as KRAS farnesylation	Homo sapiens	8.4 nM
Inhibition of farnesyltransferase (unknown origin) assessed as HRAS farnesylation	Homo sapiens	1.3 nM
Inhibition of human recombinant FTase	Homo sapiens	1.35 nM

Cross References

Resources	Reference
ChEBI	167655
ChEMBL	CHEMBL351706
DrugBank	DB12234
FDA SRS	L2U9GFD244
Guide to Pharmacology	8026
PDB	BMV
PubChem	448545
SureChEMBL	SCHEMBL94663
ZINC	ZINC000003925649

CONTENTS

Structure
Chemical and Physical Properties