Arno G. Steinig

A highly effective one-pot synthesis of quinolines from o-nitroarylcarbaldehydes.

A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).

Novel 6-aminofuro[3,2-c]pyridines as potent, orally efficacious inhibitors of cMET and RON kinases

A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.

Discovery of an Orally Efficacious Imidazo[5,1-f][1,2,4]triazine Dual Inhibitor of IGF-1R and IR.

This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacological activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is discussed.

Abstract 2915: Discovery and characterization of OSI-296, a dual inhibitor of cMET and RON kinases

cMET and RON are receptor tyrosine kinases of the MET proto-oncogene family that are activated by their respective ligands HGF and MSP. Signaling through the cMET/HGF system can be deregulated in cancer by HGF-dependent autocrine activation, gene amplification, and/or the presence of activating mutations, among others, while for RON, constitutively active variants generated by alternative splicing or methylation-dependent promoter usage [short-form RON (sfRON)] have been identified. Approaches to abrogate aberrant cMET and RON signaling that have led to agents in clinical trials include inhibiting their kinase function with small molecules. We report here the discovery and characterization of OSI-296, a dual inhibitor of cMET and RON. The compound exhibited selectivity in a panel of 96 kinases with potent activity against cMET, including common Y1230 mutants, and RON. OSI-296 blocked cMET autophosphorylation in MKN45 cells, resulting in dose-dependent inhibition of downstream ERK, AKT, and STAT3 phosphorylation. It also showed potent cellular activity in ELISA-format sfRON and caRON cell mechanistic assays that we developed, resulting in dose-dependent inhibition of downstream ERK and AKT phosphorylation. OSI-296 showed a PK profile in rodents suitable for oral dosing with >70% bioavailability. In multiple xenografts models (cMET: MKN45, SNU-5, U87MG; RON: caRON), significant tumor growth inhibition was observed upon oral dosing with regression at higher doses. OSI-296 was very well tolerated with little body weight loss and no adverse effects even at the highest tested dose of 300 mg/kg p.o. qdx14. Solid PK/PD/TGI correlations have been established wherein >90% inhibition of cMET or RON phosphorylation sustained over 24 h by OSI-296 translated to 100% TGI. In summary, OSI-296 was shown to be a well tolerated, dual inhibitor of cMET and RON with in vivo activity in mouse xenografts models for both targets upon oral dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2915. doi:1538-7445.AM2012-2915

Abstract 3900: Discovery of FQIT: An imidazo[5,1-f][1,2,4]triazine derived dual IGF-1R/IR inhibitor

Insulin-like growth factor-1 receptor (IGF-1R) has been recognized as a major target in cancer drug discovery due to its strong implications in various stages of tumorigenesis based on accumulated preclinical data over the years. Recent research on compensatory crosstalk between IGF-1R and insulin receptor (IR) signaling pathways suggests that targeting both receptors is critical to fully blocking the IGF signaling axis. Therefore, inhibition of both receptors is anticipated to result in a more therapeutically beneficial response than targeting IGF-1R alone (e.g. IGF-1R specific antibodies). These findings provided the biological rationale as well as set the foundation for the pursuit and ultimate discovery of OSI-906 (linsitinib), a small molecule dual IGF-1R/IR inhibitor currently in clinical development. As part of OSI9s ongoing investment in a small molecule drug discovery platform targeting IGF-1R and IR, a new series of potent and selective imidazo[5,1-f][1,2,4]triazine derived inhibitors of IGF-1R and IR have been identified. Structure-activity relationships and optimization driven by structure-based drug design (SBDD) leading to the discovery of FQIT, a potent, highly selective, well-tolerated and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in multiple tumor xenograft models will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3900. doi:1538-7445.AM2012-3900