Identification of pyrrolo[2,3-d]pyrimidine-based dual MERTK and FLT3 inhibitor: Hit-to-lead, machine learning, modeling, synthesis, and biological evaluation

Abstract

Overexpression of MERTK and FLT3 plays a crucial role in activating signal transduction pathways in various human hematological malignancies. These signaling pathways have been extensively studied and have shown significant potential as a promising therapeutic target for the treatment of acute myeloid leukemia (AML). In this study, we employed a modern medicinal chemistry approach, hybridizing machine learning (ML) with a bioisosterism strategy, to design and synthesize a new series of pyrrolo[2,3-d] pyridine derivatives as potent dual inhibitors of MERTK and FLT3. Through successive structure-activity relationship (SAR) studies, we successfully identified the lead compound 31l as a highly potent and selective MERTK/FLT3 dual inhibitor. Compound 31l exhibited remarkable kinase inhibitory activity against MERTK and FLT3 with IC₅₀ values of 2.58 and 0.86 nM, respectively, and potential anti-proliferative activity against MOLM-13 cell lines (IC₅₀ value of 7.50 nM). Furthermore, compound 31l displayed a favorable metabolic stability profile in both human and mouse liver microsome screens and an oral bioavailability of 56%. This finding suggests that lead compound 31l is a promising tool for further optimization and development as a potential MERTK/FLT3 dual inhibitor anti-AML drug candidate.