Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

  • ACS Med Chem Lett. 2012 Sep 24;3(12):997-1002. doi: 10.1021/ml300214g.
Gang Liu  1 ,  Brian T Campbell  1 ,  Mark W Holladay  1 ,  Julia M Ford Pulido  1 ,  Helen Hua  1 ,  Dana Gitnick  1 ,  Michael F Gardner  1 ,  Joyce James  1 ,  Mike A Breider  1 ,  Daniel Brigham  1 ,  Barbara Belli  1 ,  Robert C Armstrong  1 ,  Daniel K Treiber  1
Affiliations
  • 1. Departments of Medicinal Chemistry, Cell Biology and Pharmacology, Technology Development, and DMPK and Toxicology, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States.
PMID: 24900421 DOI: 10.1021/ml300214g
Abstract

A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

Keywords
AC710; acute myeloid leukemia (AML); cancer bone metastasis; colony-stimulating factor-1 receptor (CSF1R) inhibitor; feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3); inflammatory arthritis; platelet-derived growth factor receptor (PDGFR)-family kinases.
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