Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model
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- 作者：Wooseok Han<sup>asup><sup> ; sup> ; Daniel L. Menezes<sup>bsup> ; Yongjin Xu<sup>asup> ; Mark S. Knapp<sup>asup> ; Robert Elling<sup>asup> ; Matthew T. Burger<sup>asup> ; Zhi-Jie Ni<sup>asup> ; Aaron Smith<sup>asup> ; Jiong Lan<sup>asup> ; Teresa E. Williams<sup>asup> ; Joelle Verhagen<sup>asup> ; Kay Huh<sup>asup> ; Hanne Merritt<sup>bsup> ; John Chan<sup>bsup> ; Susan Kaufman<sup>bsup> ; Charles F. Voliva<sup>bsup> ; Sabina Pecchi<sup>asup>
- 关键词：Cancer ; Lipid kinases ; PI3K ; Pan-PI3 kinases ; Pan-PI3 kinase inhibitor ; Imidazopyridine ; Dihedral angle
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：1 February 2016
- 年：2016
- 卷：26
- 期：3
- 页码：742-746
- 全文大小：2349 K
文摘
Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound <strong class="boldFont">1strong>, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5′-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5′-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6′-Alkoxy 5′-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound <strong class="boldFont">14strong> with 1,1,1-trifluoroisopropoxy group at 6′-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound <strong class="boldFont">14strong> in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.