PO.CH01.03 · 化学
用于治疗乳腺癌的新型PI3K-CDK4/6双重抑制剂PC-13的发现与开发
Discovery and development of a novel PI3K-CDK4/6 dual inhibitor PC-13 for the treatment of breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌仍是全球癌症相关死亡的主要原因之一，凸显了对创新治疗策略的迫切需求。在本研究中，我们报道了PC-13的发现及临床前表征，PC-13是一种潜在的同类首创（first-in-class）双重抑制剂，同时靶向PI3K和CDK4/6。PC-13对PI3K和CDK4/6激酶表现出纳摩尔级效力，在广泛的激酶谱中具有高选择性，并在多种乳腺癌细胞系中具有强效抗增殖作用。此外，PC-13表现出合理的药代动力学特性，并在T47D异种移植模型中实现了显著的肿瘤生长抑制，疗效可与Palbociclib-Buparlisib联合方案相媲美，同时保持了良好的安全性。我们的研究结果突显了同时抑制PI3K和CDK4/6作为一种新颖有效的乳腺癌治疗方法的潜力，支持将PC-13作为临床候选药物进一步开发。
查看英文原文 English abstract
Breast cancer continues to be a major cause of cancer-associated mortality globally, underscoring the urgent need for innovative therapeutic strategies. In this study, we report the discovery and preclinical characterization of PC-13, a potential first-in-class dual inhibitor targeting both PI3K and CDK4/6. PC-13 demonstrates nanomolar-level potency against PI3K and CDK4/6 kinases, high selectivity across a broad panel of kinases, and potent antiproliferative effects in multiple breast cancer cell lines. Furthermore, PC-13 exhibits reasonable pharmacokinetic properties and achieves significant tumor growth suppression in a T47D xenograft model, with efficacy comparable to the Palbociclib-Buparlisib combination regimen, while maintaining a promising safety profile. Our findings highlight the potential of concurrent PI3K and CDK4/6 inhibition as a novel and effective therapeutic approach for breast cancer, supporting further development of PC-13 as a clinical candidate.
利益披露 Disclosure
X. Zhang, None..
J. Hu, None..
X. Li, None..
Q. Wang, None..
Y. Zhao, None..
Q. Xia, None..
J. Wang, None..
H. Xu, None..
T. Bing, None.