Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

  • J Med Chem. 2020 Sep 10;63(17):9888-9911. doi: 10.1021/acs.jmedchem.0c00936.
Barbara Czako  1 ,  Joseph R Marszalek  2 ,  Jason P Burke  1 ,  Pijus Mandal  1 ,  Paul G Leonard  1 ,  Jason B Cross  1 ,  Faika Mseeh  1 ,  Yongying Jiang  1 ,  Edward Q Chang  2 ,  Erika Suzuki  2 ,  Jeffrey J Kovacs  2 ,  Ningping Feng  2 ,  Sonal Gera  2 ,  Angela L Harris  2 ,  Zhen Liu  1 ,  Robert A Mullinax  2 ,  Jihai Pang  1 ,  Connor A Parker  1 ,  Nakia D Spencer  2 ,  Simon S Yu  1 ,  Qi Wu  1 ,  Martin R Tremblay  3 ,  Keith Mikule  3 ,  Keith Wilcoxen  3 ,  Timothy P Heffernan  2 ,  Giulio F Draetta  4 ,  Philip Jones  1
Affiliations
  • 1. IACS (Institute of Applied Cancer Science), University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.
  • 2. TRACTION (Translational Research to AdvanCe Therapeutics and Innovation in Oncology), University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.
  • 3. Tesaro Inc., 1000 Winter Street, Waltham, Massachusetts 02451, United States.
  • 4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
PMID: 32787110 DOI: 10.1021/acs.jmedchem.0c00936
Abstract

Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.

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