Jerry Cohen

Publications (12)30.64 Total impact

• Article: A highly potent and selective farnesyltransferase inhibitor ABT-100 in preclinical studies.

  Wen-Zhen Gu, Ingrid Joseph, Yi-Chun Wang, David Frost, Gerard M Sullivan, Le Wang, Nan-Horng Lin, Jerry Cohen, Vincent S Stoll, Clarissa G Jakob, [......], Mark G Anderson, Paul Kroeger, Luis E Rodriguez, Kenneth P Jarvis, Debra Ferguson, Kennan Marsh, Shichung Ng, Saul H Rosenberg, Hing L Sham, Haiying Zhang
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  ABSTRACT: Ras mutation has been detected in approximately 20-30% of all human carcinomas, primarily in pancreatic, colorectal, lung and bladder carcinomas. The indirect inhibition of Ras activity by inhibiting farnesyltransferase (FTase) function is one therapeutic intervention to control tumor growth. Here we report the preclinical anti-tumor activity of our most advanced FTase inhibitor (FTI), ABT-100, and a direct comparison with the current clinical candidates. ABT-100 is a highly selective, potent and orally bioavailable FTI. It broadly inhibits the growth of solid tumors in preclinical animal models. Thus, ABT-100 is an attractive candidate for further clinical evaluation. In addition, our results provide plausible insights to explain the impressive potency and selectivity of ABT-100. Finally, we have demonstrated that ABT-100 significantly suppresses the expression of vascular endothelial growth factor (VEGF) mRNA and secretion of VEGF protein, as well as inhibiting angiogenesis in the animal model.
  Anti-Cancer Drugs 12/2005; 16(10):1059-69. · 2.41 Impact Factor
• Article: Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity.

  Qun Li, Tongmei Li, Keith W Woods, Wen-Zhen Gu, Jerry Cohen, Vincent S Stoll, Tomas Galicia, Charles Hutchins, David Frost, Saul H Rosenberg, Hing L Sham
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  ABSTRACT: A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC(50) values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC(50) values of 18 and 22nM, respectively.
  Bioorganic & Medicinal Chemistry Letters 07/2005; 15(11):2918-22. · 2.55 Impact Factor
• Article: Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors.

  Qun Li, Keith W Woods, Weibo Wang, Nan-Horng Lin, Akiyo Claiborne, Wen-zhen Gu, Jerry Cohen, Vincent S Stoll, Charles Hutchins, David Frost, Saul H Rosenberg, Hing L Sham
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  ABSTRACT: Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.
  Bioorganic & Medicinal Chemistry Letters 05/2005; 15(8):2033-9. · 2.55 Impact Factor
• Article: Design and synthesis of o-trifluoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of farnesyltransferase.

  Gary T Wang, Xilu Wang, Weibo Wang, Lisa A Hasvold, Gerry Sullivan, Charles W Hutchins, Steve O'Conner, Robert Gentiles, Thomas Sowin, Jerry Cohen, Wen-Zhen Gu, Haiying Zhang, Saul H Rosenberg, Hing L Sham
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  ABSTRACT: A non-methionine FT inhibitor lead structure (1) was designed through computer modeling of the peptidomimetic FT inhibitor ABT839. Optimization of this lead resulted in compounds 2e and 2g, with FT IC(50) values of 1.3 and 1.8 nM, GGT IC(50) of 1400 nM, and EC(50) (Ras processing) values of 13 and 11 nM, respectively.
  Bioorganic & Medicinal Chemistry Letters 02/2005; 15(1):153-8. · 2.55 Impact Factor
• Article: Synthesis and activity of 1-aryl-1'-imidazolyl methyl ethers as non-thiol farnesyltransferase inhibitors.

  Qun Li, Gary T Wang, Tongmei Li, Stephen L Gwaltney, Keith W Woods, Akiyo Claiborne, Xilu Wang, Wendy Gu, Jerry Cohen, Vincent S Stoll, Charles Hutchins, David Frost, Saul H Rosenberg, Hing L Sham
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  ABSTRACT: A series of imidazole-containing methyl ethers (4-5) have been designed and synthesized as potent and selective farnesyltransferase inhibitors (FTIs) by transposition of the D-ring to the methyl group on the imidazole of the previously reported FTIs 3. Several compounds such as 4h and 5b demonstrate superior enzymatic activity to the current benchmark compound tipifarnib (1) with IC(50) values in the lower subnanomolar range, while maintaining excellent cellular activity comparable to tipifarnib. The compounds are characterized as being simple, easier to make, and possess no chiral center involved.
  Bioorganic & Medicinal Chemistry Letters 12/2004; 14(21):5371-6. · 2.55 Impact Factor
• Article: Design, synthesis, and activity of 4-quinolone and pyridone compounds as nonthiol-containing farnesyltransferase inhibitors.

  Qun Li, Akiyo Claiborne, Tongmei Li, Lisa Hasvold, Vincent S Stoll, Steven Muchmore, Clarissa G Jakob, Wendy Gu, Jerry Cohen, Charles Hutchins, David Frost, Saul H Rosenberg, Hing L Sham
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  ABSTRACT: As a part of our efforts to identify potent inhibitors of farnesyltransferase (FTase), modification of the structure of tipifarnib through structure-based design was undertaken by replacing the 2-quinolones with 4-quinolones and pyridones, and subsequent relocation of the D-ring to the N-methyl group on the imidazole ring. This study has yielded a novel series of potent and selective FTase inhibitors. The X-ray structure of tipifarnib (1) in complex with FTase was described.
  Bioorganic & Medicinal Chemistry Letters 12/2004; 14(21):5367-70. · 2.55 Impact Factor
• Article: Synthesis and biological evaluation of 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole as novel farnesyltransferase inhibitor.

  Nan-Horng Lin, Le Wang, Xilu Wang, Gary T Wang, Jerry Cohen, Wen-Zhen Gu, Haiying Zhang, Saul H Rosenberg, Hing L Sham
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  ABSTRACT: Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anti-cancer agents. Analogs of the potent FTI, 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole, were synthesized and tested in vitro for their inhibitory activities. The most promising compound identified from this series is analog 29 that possesses potent enzymatic and cellular activities.
  Bioorganic & Medicinal Chemistry Letters 11/2004; 14(20):5057-62. · 2.55 Impact Factor
• Article: 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.

  Le Wang, Gary T Wang, Xilu Wang, Yunsong Tong, Gerry Sullivan, David Park, Nicholas M Leonard, Qun Li, Jerry Cohen, Wen-Zhen Gu, Haiying Zhang, Joy L Bauch, Clarissa G Jakob, Charles W Hutchins, Vincent S Stoll, Kennan Marsh, Saul H Rosenberg, Hing L Sham, Nan-Horng Lin
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  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).
  Journal of Medicinal Chemistry 02/2004; 47(3):612-26. · 5.25 Impact Factor
• Article: Synthesis and biological evaluation of 4-[(3-methyl-3H-imidazol-4-yl)-(2-phenylethynyl-benzyloxy)-methyl]-benzonitrile as novel farnesyltransferase inhibitor.

  Nan-Horng Lin, Le Wang, Jerry Cohen, Wen-Zhen Gu, David Frost, Haiying Zhang, Saul Rosenberg, Hing Sham
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  ABSTRACT: Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anticancer agents. Analogues of the potent FTI, 4-[3-biphenyl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile, were synthesized and tested in vitro for their inhibitory activities. The most promising compound identified from this series is analogue 11 that possesses potent enzymatic and cellular activities.
  Bioorganic & Medicinal Chemistry Letters 12/2003; 13(21):3821-5. · 2.55 Impact Factor
• Article: Discovery of potent imidazole and cyanophenyl containing farnesyltransferase inhibitors with improved oral bioavailability.

  Yunsong Tong, Nan-Horng Lin, Le Wang, Lisa Hasvold, Weibo Wang, Nicholas Leonard, Tongmei Li, Qun Li, Jerry Cohen, Wen-Zhen Gu, Haiying Zhang, Vincent Stoll, Joy Bauch, Kennan Marsh, Saul H Rosenberg, Hing L Sham
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  ABSTRACT: A pyridyl moiety was introduced into a previously developed series of farnesyltransferase inhibitors containing imidazole and cyanophenyl (such as 4), resulting in potent inhibitors with improved pharmacokinetics.
  Bioorganic & Medicinal Chemistry Letters 06/2003; 13(9):1571-4. · 2.55 Impact Factor
• Article: Synthesis and biological evaluation of 4-[3-biphenyl-2-yl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile as novel farnesyltransferase inhibitor.

  Nan-Horng Lin, Le Wang, Jerry Cohen, Wen-Zhen Gu, David Frost, Haiying Zhang, Saul Rosenberg, Hing Sham
  [show abstract] [hide abstract]
  ABSTRACT: Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anti-cancer agents. Analogues of the potent FTI, 4-[3-biphenyl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile, were synthesized and tested in vitro for their inhibitory activities. The synthesis and detailed biological data of this series of analogues are presented.
  Bioorganic & Medicinal Chemistry Letters 05/2003; 13(7):1293-6. · 2.55 Impact Factor
• Article: (1α,2β,3β,4α)-1,2-Bis[[N-propyl-N-(4-phen- oxybenzyl)amino]carbonyl]cyclobutane- 3,4-dicarboxylic Acid (A-87049):  A Novel Potent Squalene Synthase Inhibitor

  Anthony K. L. Fung, William R. Baker, Steven Fakhoury, Herman H. Stein, Jerry Cohen, Bernard G. Donner, David S. Garvey, Kenneth P. Spina, Saul H. Rosenberg
  07/1997;