DCLK1-IN-1

DCLK1-IN-1 is a highly potent and selective small molecule kinase inhibitor targeting doublecortin-like kinase 1 (DCLK1) and doublecortin-like kinase 2 (DCLK2). It was developed by the Nathanael S. Gray laboratory at Dana-Farber Cancer Institute using chemoproteomic profiling and structure-guided inhibitor design[1]. The compound exhibits IC50 values of 9.5 nM and 57.2 nM for DCLK1, and 31 nM and 103 nM for DCLK2[8]. DCLK1-IN-1 demonstrates pronounced selectivity, exclusively inhibiting DCLK1 and DCLK2 in kinome-wide screening at 1 μM concentration, with no significant off-target effects on ERK5, ACK, LRRK2, or BRD4 bromodomain[1]. The compound was specifically designed to overcome the limitations of previous DCLK1 inhibitors like LRRK2-IN-1, which had significant off-target effects. Structurally, DCLK1-IN-1 belongs to the 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one class and features a trifluoroethyl group that is crucial for its selectivity profile[1]. The binding of DCLK1-IN-1 induces a conformational change in the ATP binding site of DCLK1[4]. DCLK1-IN-1 has demonstrated efficacy in preclinical studies for pancreatic ductal adenocarcinoma (PDAC), renal cell carcinoma (RCC), colorectal cancer (CRC), and gastric cancer, where it inhibits cancer stem cell properties, invasion, migration, and colony formation[1][2]. In RCC, DCLK1-IN-1 has shown immunotherapeutic properties by reducing PD-L1 expression and enhancing T-cell-mediated cytotoxicity, with synergistic effects when combined with anti-PD1 therapy[2].