Guoqing Cao

Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model.

This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC50 of 33.7nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).

WITHDRAWN: Discovery of SHR1977: A highly potent and selective ROMK inhibitor.

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Abstract C254: Discovery of a novel and potent BRAF (V600E) inhibitor with a unique kinase targeting profile, EBI-907: Pharmacological characterization and potential to overcome drug resistance and paradoxical activation.

The RAS/RAF/MEK/ERK pathway plays a central role in regulating cell proliferation, differentiation, and growth. The oncogenic mutation of BRAF (V600E) has been found in 8% of all human cancers, including more than 60% of melanoma, 45% of papillary thyroid cancer, 10% of colorectal cancers, and a small subset of ovarian, breast, lung cancers, and leukemia. Although BRAF-specific inhibitors such as Vemurafenib (PLX-4032) and Dabrafenib (GSK2118436) have been approved by FDA and several other BRAF inhibitors are at different stages of clinical development, they carry some liabilities and drug resistance rapidly developed. We have sought to identify and develop more potent BRAF (V600E) inhibitors with favorable pharmacological and safety profiles. Our chemistry effort has led to the discovery of EBI-907 as a novel BRAF (V600E) inhibitor with potent anti-tumor activity in vitro and in vivo. In a LanthaScreen BRAF (V600E) kinase assay, EBI-907 is a highly potent inhibitor displaying a low single-digit nanomolar activity (IC50 = 4.9 nM), which is >10-fold more potent than Vemurafenib (IC50 = 59 nM). EBI-907 also exhibits high potency in selectively inhibiting the proliferation of BRAF (V600E)-dependent cell lines (A375 and Colo205) and cellular Erk phosporylation, with superior activity to Vemurafenib. In multiple preclinical species (mice, rats, and dogs), EBI-907 exhibited an excellent oral bioavailability. In a BRAF (V600E)-dependent human Colo-205 tumor xenograft mouse model, EBI-907 caused a partial or complete tumor regression in a dose-dependent manner, with superior efficacy than Vemurafenib. In addition, we have also observed a broader kinase selectivity profile for EBI-907, displaying potent activity against a number of important oncogenic kinases including BRK, FGFR1, c-Kit, and PDGFRb. Preliminary toxicity studies in rodent models showed that EBI-907 was well tolerated and has a high safety margin. More importantly, EBI-907 showed a favorable pattern of drug-induced paradoxical activation of MAPK pathway, pointing to a possibility to “break” the inhibitor paradox. Finally, our results showed that combined use of EBI-907 and a MEK inhibitor completely abolished the paradoxical activation and overcame the drug resistance induced by BRAF inhibitor alone. Our findings not only present EBI-907 as a potent and promising BRAF inhibitor, but also point out a possibility to develop next generation targeted therapies to treat BRAF mutated cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C254. Citation Format: Jiayin Zhang, Dong Liu, Ru Shen, Yinfa Yan, Liuqing Yang, Minsheng Zhang, Guoqing Cao, Hu Cao, Beibei Fu, Aishen Gong, Biao Lu, Qiming Sun, Hong Wan, Pangke Yan, Lei Zhang, Lianshan Zhang, Jingsong Cao. Discovery of a novel and potent BRAF (V600E) inhibitor with a unique kinase targeting profile, EBI-907: Pharmacological characterization and potential to overcome drug resistance and paradoxical activation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C254.