Abstract 4021: CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors

Abstract We identified CTS2016 as a novel, selective, orally bioavailable small molecule inhibitor with single-digit nanomolar enzymatic activity to AXL and FLT3. Overexpression of AXL is associated with metastasis, drug resistance, and poor prognosis of various hematological and solid tumors, which are all broadly modulated with epigenetic regulation. In addition, inhibition of AXL phosphorylation may overcome drug resistance to current FLT3 inhibitors in FLT3-ITD+ Acute Myeloid Leukemia (AML) (Park et al., 2015). We tested CTS2016 as a single agent or in combination with either venetoclax, a Bcl-2 inhibitor, or azacitidine, a hypomethylating agent (HMA) and an epigenetic modulation drug, in a series of in vitro and in vivo studies using various AML models CTS2016 resulted in a potent growth inhibitory effect with strong induction of cell death in a spectrum of AML cell lines carrying FLT3 mutations (FLT3-ITD and/or FLT3-TKD) CTS2016 orally administered once daily, demonstrated potent and dose-dependent antitumor responses in a variety of AML xenograft mouse models. The anti-tumor activity was correlated with the inhibition of receptor tyrosine kinase signaling, as measured by decreased phosphorylation of key downstream signaling targets of FLT3. In a tail vein injection of mouse LLC-Luciferase model, CTS2016 treatment could significantly reduce tumor metastasis. A combination of CTS2016 with venetoclax or azacitidine provides a therapeutic benefit over monotherapy and supports a rationale for testing these combination therapies in patients with relapsed or refractory (R/R) AML and myelodysplastic syndromes (MDS). In addition, CTS2016 significantly reduced the tumor burden of a leukemia model harboring FLT3-ITD-F691L, a drug-resistant mutation of FLT3. Notably, the selectivity of CTS2016 over other kinases (such as c-KIT) mitigates the off-target toxicity effects on normal hematological differentiation which is common in clinics for other FLT3 inhibitors. These data demonstrate that CTS2016 could be a promising therapy for treating patients diagnosed with AML and MDS harboring FLT3 mutations and solid tumors such as NSCLC and TNBC with high-expression of AXL. More proof-of-concept data would come from the ongoing clinical trial. Citation Format: Hui Shi, Meng Wang, Jiaxin Huang, Qiugeng Ouyang, Jiannan Guo, Youzhen Wang, Yuan Mi, Haiping Wu. CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4021.