Insilico Medicine Shanghai Ltd

Through structure-based design to optimize protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) inhibitors, we developed two distinct conformational restriction strategies: intermolecular hydrogen bonding and cyclization. The hinge-binding carboxamide cyclized derivative B3 demonstrated potent enzymatic inhibition (IC₅₀ = 3.5 nM) and cellular CDK1 phosphorylation suppression (IC₅₀ = 65-114 nM), selectively inhibited proliferation of CCNE1-amplified cancer cells (IC₅₀ = 0.56-0.88 μM) through induction of γH2AX accumulation. Furthermore, compared to the first-in-class PKMYT1 inhibitor RP-6306, B3 exhibited enhanced solubility (176 vs 45 μM) and favorable in vivo metabolic stability (mouse clearance 58.2 vs 85.7 mL/min/kg), underscoring cyclization as a productive design strategy to improve drug-likeness of PKMYT1 inhibitors.

Cyclin-dependent kinases (CDKs) are central regulators of the cell cycle progression and transcription, making them attractive targets especially in oncology. The clinical success of CDK4/6 inhibitors in hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer has highlighted the therapeutic potential of CDK inhibition, along with ongoing clinical evaluation of other CDK-targeted agents. Despite the progress, challenges still remain due to off-target toxicity and the emergence of resistance. Recently, macrocycle-based drug design has gained recognition for its ability to enhance the kinase inhibitory activities and selectivity, improve drug-like properties, and potentially overcome resistance. This review summarizes recent advances (2015-2025) in macrocyclization strategies for CDK inhibitors, tracing the structural modification process from the acyclic scaffolds and highlighting their potential to address key limitations of current therapies.

The diacylglycerol kinase alpha (DGKα) is an important player in signal transduction, phosphorylating the membrane lipid diacylglycerol to phosphatidic acid. Emerging data indicate that DGKα mediates T cell dysfunction during anti-PD-1 therapy, having a marked impact on the development of resistance to PD-1 blockade. Here, we report the discovery of compound 10 as a novel, potent, selective, and orally available DGKα inhibitor with a promising ADME profile. More importantly, compound 10 significantly enhanced the in vivo antitumor activities by combination with anti-PD-1 or anti-CTLA-4 in different mouse models, and obvious synergistic effects were observed.