2. Academic Validation
  3. Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

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

Affiliation

  • 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.

Figures
Products