100959-51-1Relevant articles and documents
Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R
Czako, Barbara,Marszalek, Joseph. R.,Burke, Jason P.,Mandal, Pijus,Leonard, Paul G.,Cross, Jason B.,Mseeh, Faika,Jiang, Yongying,Chang, Edward Q.,Suzuki, Erika,Kovacs, Jeffrey J.,Feng, Ningping,Gera, Sonal,Harris, Angela L.,Liu, Zhen,Mullinax, Robert A.,Pang, Jihai,Parker, Connor A.,Spencer, Nakia D.,Yu, Simon S.,Wu, Qi,Tremblay, Martin R.,Mikule, Keith,Wilcoxen, Keith,Heffernan, Timothy P.,Draetta, Giulio F.,Jones, Philip
, p. 9888 - 9911 (2020)
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.
Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors
Kohlmann, Anna,Zech, Stephan G.,Li, Feng,Zhou, Tianjun,Squillace, Rachel M.,Commodore, Lois,Greenfield, Matthew T.,Lu, Xiaohui,Miller, David P.,Huang, Wei-Sheng,Qi, Jiwei,Thomas, R. Mathew,Wang, Yihan,Zhang, Sen,Dodd, Rory,Liu, Shuangying,Xu, Rongsong,Xu, Yongjin,Miret, Juan J.,Rivera, Victor,Clackson, Tim,Shakespeare, William C.,Zhu, Xiaotian,Dalgarno, David C.
, p. 1023 - 1040 (2013/03/28)
Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (Kd) and enzyme inhibition (IC 50) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.
