2. Academic Validation
  3. Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153243
    CSF1R Inhibitor