Discovery of a 2,4-disubstituted pyrrolo-[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development

Journal of Medicinal Chemistry

Volumn 52, Issue 23, 2009, Pages 7360-7363

  Wittman, Mark D ^a   Carboni, Joan M ^a   Yang, Zheng ^a   Lee, Francis Y ^a   Antman, Melissa ^a   Attar, Ricardo ^a   Balimane, Praveen ^a   Chang, Chiehying ^a   Chen, Cliff ^a   Discenza, Lorell ^a   Frennesson, David ^a   Gottardis, Marco M ^a   Greer, Ann ^a   Hurlburt, Warren ^a   Johnson, Walter ^a   Langley, David R ^a   Li, Aixin ^a   Li, Jianqing ^a   Liu, Peiying ^a   Mastalerz, Harold ^a   Mathur, Arvind ^a   Menard, Krista ^a   Patel, Karishma ^a   Sack, John ^a   Sang, Xiaopeng ^a   Saulnier, Mark ^a   Smith, Daniel ^a   Stefanski, Kevin ^a   Trainor, George ^a   Velaparthi, Upender ^a   Zhang, Guifen ^a   Zimmermann, Kurt ^a   Vyas, Dolatrai M ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BMS 754807; SOMATOMEDIN C RECEPTOR; TRIAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; MOUSE; NONHUMAN; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; TREATMENT OUTCOME;

ANIMALS; BIOMEDICAL RESEARCH; DOGS; DRUG DISCOVERY; HUMANS; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEIN KINASE INHIBITORS; PYRAZOLES; RATS; RECEPTOR, IGF TYPE 1; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZINES;

EID: 72249089981     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900786r     Document Type: Article

References (14)

1. Salmon, W. D.; Daughaday, W. H. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J. Lab. Clin. Med. 1957, 49, 825-836.
2. Arteaga, C. L.; Kitten, L. J.; Coronado, L .J.; Jacobs, S.; Kull, F. C., Jr.; Allred, D. C.; Osborne, C. K. Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J. Clin. Invest. 1989, 84, 1418-1423.
3. Chan, J. M.; Stampfer, M. J.; Giovannucci, E.; Gann, P. H.; Ma, J.; Wilkinson, P.; Hennekens, C. H.; Pollak, M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998, 279, 563-566. (Pubitemid 28067285)
4. Skolnik, E. Y.; Lee, C. H.; Batzer, A.; Vicentini, L. M. The SH2/ SH3 domain-containing protein GRB2 interacts with tyrosinephosphorylated IRS1 and Shc: implications for insulin control of ras signaling. EMBO J. 1993, 12, 1929-1936. (Pubitemid 23157709)
5. Vanhaesebroeck, B.; Alessi, D. R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 2000, 346, 561-576.
6. Buck, E.; Eyzaguirre, A.; Rosenfeld-Franklin, M.; Thomson, S.; Mulvihill, M.; Barr, S.; Brown, E.; O'Connor, M.; Yao, Y.; Pachter, J.; Miglarese, M.; Epstein, D.; Iwata, K. K.; Haley, J. D.; Gibson, N. W.; Ji, Q.-S. Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. Cancer Res. 2008, 68, 8322-8332.
7. Camirand, A.; Zakikhani, M.; Young, F.; Pollak, M. Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells. Breast Cancer Res. 2005, 7, R465-R474.
8. Morgillo, F.; Woo, J. K.; Kim, E. S.; Hong, W. K.; Lee, H. Y. Heterodimerization of insulin-like growth factor receptor/ epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res. 2006, 66, 10100-10111.
9. Arnold, L. D.; Cesario, C.; Coate, H.; Crew, A. P.; Dong, H.; Foreman, K.; Honda, A.; Laufer, R.; Li, A.-H.; Mulvihill, K. M.; Mulvihill, M. J.; Nigro, A.; Panicker, B.; Steinig, A. G.; Sun, Y.; Weng, Q.; Werner, D. S.; Wyle, M. J.; Zhang, T. Patent Application WO2005/097800, 2005.
10. Volk, B.; Buck, E.; Coate, H.; Cooke, A.; Dong, H.; Eyzaguirre, A.; Feng, L.; Foreman, K.; Rosenfeld-Franklin, M.; Kleinberg, A.; Landfair, D.; Mak, G.; Nigro, A.; O'Connor, M.; Pirritt, C.; Silva, S.; Siu, K.; Steinig, A.; Stolz, K.; Tavares-Greco, P.; Turton, R.; Werner, D.; Yao, Y.; Arnold, L.; Gibson, N. W.; Pachter, J. A.; Wild, R.; Ji, Q.-S.; Mulvihill, M. J. OSI - 906: A Novel, Potent, and Selective First-in-Class Small Molecule Insulin-like Growth Factor 1 Receptor (IGF-1R) Inhibitor in Phase I Clinical Trials. Abstracts of Papers, 238th National Meeting of the American Chemical Society, Washington, DC, August 16-20, 2009; MEDI-152.
11. Carboni, J. M.; Lee, A. V.; Hadsell, D. L.; Rowley, B. R.; Lee, F. Y.; Bol, D. K.; Camuso, A. E.; Gottardis, M.; Greer, A. F.; Ho, C. P.; Hurlburt, W.; Li, A.; Saulnier, M.; Velaparthi, U.; Wang, C.; Wen, M.-L.; Westhouse, R. A.; Wittman, M.; Zimmermann, K.; Rupnow, B. A.; Wong, T. W. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer. Res. 2005, 65, 3781-3787.
12. i (within 2×). (13) %TGI = [(tumor size of control group at end of treatment) - (tumor size of treated group at the end of treatment)]/[(tumor size of control group at end of treatment) - (tumor size of control group at the start of treatment)]. %TGI > 50% is considered active. Each treatment group consisted of 6 mice. Tumors were measured on day 0 and day 4.
13. Mice were dosed orally with 9d at 3.125, 6.25, and 12.5 mg/kg b.i.d. for 4 days. On day 5, a final dose of compound was administered to mice and the tumors were excised after 2 h. The effect of 9d on pIGF-1R and pAkt activity was monitored by Western blot analysis using antibodies specific to IGF-1R and Akt.
14. Carboni, J. M.; Wittman, M.; Yang, Z.; Lee, F.; Greer, A.; Hurlburt, W.; Hillerman, S.; Cao, C.; Cantor, G.; Chen, C.; Discenza, L.; Menard, K.; Li, A.; Trainor, G.; Vyas, D.; Kramer, R.; Attar, R.; Gottardis, M. BMS-754807, a small molecule inhibitor of IGF-1R/IR Mol. Cancer Ther., in press.