Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD₅₀ > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t_1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.

多发性骨髓瘤（MM）在恶性造血癌中排名第二，最常见的抗MM药物容易产生耐药性。CDK4/6 已被证实在 MM 中起决定性作用，但针对 MM 的 CDK4/6 抑制剂的临床试验并未取得显着进展。为了发现具有更好效力和高成药性的新型CDK6抑制剂，进行了基于结构的虚拟筛选以鉴定化合物10。进一步的化学优化提供了更好的衍生物化合物32，它表现出对 CDK4/6 的强抑制作用，并对 360 多种激酶（包括同源 CDK）表现出高选择性。体内评估表明化合物32具有低毒性 (LD ₅₀ > 10,000 mg/kg)、良好的生物利用度 (F% = 51%)、高代谢稳定性 (t _1/2  > 24 h) 和强大的抗 MM 效力。总之，我们发现了一种具有良好药物样特性的新型 CDK4/6 抑制剂，并为 MM 临床前研究提供了一个很好的候选者。