George T. Topalov

Potent and selective pyrazole-based inhibitors of B-Raf kinase

Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies.

Non-oxime pyrazole based inhibitors of B-Raf kinase.

The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.

Discovery of a Novel Class of Imidazo[1,2-a]Pyridines with Potent PDGFR Activity and Oral Bioavailability.

The in silico construction of a PDGFRβ kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted in significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.

Abstract 551: A potent and selective cFMS inhibitor regulates the tumor macrophage microenvironment leading to tumor growth inhibition

Increasing evidence suggests that interactions between tumor cells, stromal cells, macrophages and the extracellular matrix are pivotal to the processes of tumorigenesis, metastasis, and neovascularization. Macrophages within the tumor microenvironment are thought to facilitate cancer progression, making them intriguing targets for therapy. Colony stimulating factor 1 (CSF-1) and its receptor, cFMS, play a central role in the development of mononuclear phagocytes, recruitment of macrophages to tumors, and differentiation and function of osteoclasts. We have developed an orally active, selective small-molecule cFMS inhibitor for cFMS. This molecule inhibits cFMS cellular activity (IC 50 = 9 nM) in vitro and inhibits cFMS phosphorylation in a transfected cell line grown in nude mice (ED 50 = 3 mg/kg). Our compound also inhibits CSF-1-mediated osteoclast differentiation and function (IC 50 values of = 4 nM and 58 nM, respectively). To further explore the potential of our selective inhibitor for the treatment of cancer, we evaluated anti-tumor activity in several preclinical models. We first explored the effect on the murine ovarian cancer cell line, ID8. ID8 cells injected intraperitoneally into nude mice form multiple peritoneal tumor deposits and abundant ascites. Macrophage infiltration in the ID8 ascites was markedly lowered in mice treated with a cFMS inhibitor. Using MCF-7, a human breast adenocarcinoma cell line that has been shown to produce M-CSF, a daily oral dose with 100 mg/kg of our inhibitor for 21 days significantly reduced tumor growth and was accompanied by a marked reduction in tumor-associated macrophages. These findings support the potential of a selective inhibitor of cFMS to favorably impact human cancers by modulating tumor-associated macrophage functions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 551. doi:10.1158/1538-7445.AM2011-551