AXLMERTK are members of TAM (TYRO3, AXLMERTK) receptor tyrosine kinases. Both AXLMERTK play important roles in tumor progression, metastasis, drug resistanceimmune evasion. This invention describes the discoverydevelopment of BPR5K230, a potent, orally bioavailable AXLMERTK dual kinase inhibitor with anti-tumor efficacyimmunomodulatory activities. The current invention is most suitable for patients who fail current therapieswhose tumorsimmune cells overexpress AXLMERTK. The current invention represents a novel target-driven, patient-stratified precision cancer medicine for tough-to-treat cancers.

We have identified a potent AXLMERTK dual kinase inhibitor BPR5K230 from our proprietary small molecule kinase inhibitors compound libraryoptimized through structure-based drug design by protein crystallography approach. BPR5K230 demonstrated in vivo anti-tumor efficacyimmunomodulatory activitieswas more efficacious in inhibiting tumor growth than the clinical stage dual AXLMERTK inhibitor Ono-7475. BPR5K230 produced greater anti-tumor efficacy than either AXLMERTK mono-targeted agent used alone, verifying BPR5K230’s dual AXLMERTK inhibitory activities. In addition, BPR5K230 re-sensitized erlotinib-resistant tumors to erlotinib. BPR5K230 was orally bioavailableexhibited good safety profiles in mice.

Novel AXLMERTK dual kinase inhibitors use one single chemical entity with dual functions to simultaneously inhibit AXLMERTK signaling in the tumortumor immune suppressive microenvironment, thereby enhancing anti-tumor efficacyboosting anti-tumor immune responses. AXLMERTK dual kinase inhibitors are best used for cancer types that are difficult to treatprone to treatment resistancerecurrence. Novel AXLMERTK dual kinase inhibitors can be positioned in kinase inhibitors markets, targeted cancer therapy marketimmuno-oncology market. We expect that AXLMERTK dual kinase inhibitors will drive the growth of biotechnologypharmaceutical industries to increase the demand for such cancer drugs.