Abstract LB-288: A highly selective small molecule CSF-1R inhibitor demonstrates strong immunomodulatory activity in syngeneic models
Authors: Yang Shuqun , Zhao Baowei , Zhang Mingming , Zhao Yuan , Chen Xin , Zhang Lei , Yu Hongping , Chen Zhui , Xu Yaochang 
Published: August 2018

Abstract
Introduction: CSF-1R is the receptor for Colony-Stimulating Factor 1 (CSF-1), which belongs to the type III protein tyrosine kinase family. CSF-1R signaling is critical for macrophage/myeloid-derived suppressing cells (MDSC) recruitment, proliferation, and survival. Inhibition of CSF-1R leads to the reduction and repolarization of macrophages and MDSCs in tumor microenvironment, offering potential combinatory synergy with immune-oncology checkpoint antibodies for the treatment of multiple cancers. By using state-of-art computational structure analysis and medicinal chemistry design, we have discovered a novel, highly selective, and potent small molecule CSF-1R inhibitor, ABSK-021.
Method: ABSK-021 was evaluated in biochemical ADP-Glo assay and Cell-Titer Glo assay for its inhibition on CSF-1R enzymatic activity and cellular proliferation. Its selectivity against other receptor tyrosine kinases was analyzed by ELISA, cellular proliferation, and KinomeScan assays. The pharmacokinetics (PK) profile of ABSK-021 was characterized in four species of animals (mouse, rat, dog, monkey). Efficacy studies were conducted in two syngeneic models, and flow cytometry analysis was performed in tumor-bearing mice after short term dosing. Its preliminary toxicity profile was also generated by several classical safety assays.
Results: ABSK-021 has potent biochemical and cellular activities against CSF-1R (IC50&lt;30 nM), resulting in strong inhibition of CSF-1R phosphorylation and the proliferation of bone-marrow derived macrophage at low nM concentration. ABSK-021 has over 40-fold selectivity against KIT/FLT3/PDGFR-alpha/VEGFR2, which are in the same tyrosine kinase family with CSF-1R. KinomeScan also revealed its excellent selectivity against other receptor tyrosine kinases. In vivo PK study demonstrated high exposure and superior DMPK profile of ABSK-021 in mouse, rat, dog, and monkey. Efficacy studies showed that ABSK-021 strongly enhanced anti-tumor efficacy of anti-PD-1 antibody in syngeneic models. Reduction of tumor-associated macrophage and MDSC after ABSK-021 dosing was confirmed by flow cytometry analysis. Safety studies showed that ABSK-021 has no inhibition on CYP family members, hERG, and other 43 safety targets in CEREP's SafetyScreen panel (IC50&gt;10 μM).
Conclusion: ABSK-021, presented here by Abbisko Therapeutics, is a highly potent, selective, and oral-available small molecule CSF-1R inhibitor. Its superior profile supports fast-track preclinical development.
Citation Format: Shuqun Yang, Baowei Zhao, Mingming Zhang, Yuan Zhao, Xin Chen, Lei Zhang, Hongping Yu, Zhui Chen, Yaochang Xu. A highly selective small molecule CSF-1R inhibitor demonstrates strong immunomodulatory activity in syngeneic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-288.