Yang Guiqun, Lin Yiwei, Sun Xin, Cheng Dai, Li Haijun, Hu Shizong, Chen Mingming, Wang Yinxiang, Wang Yanping
Jacobio Pharmaceuticals Co., Ltd., 105 Jinghai Third Street, Beijing 100176, China.
ACS Omega. 2024 May 3;9(19):21416-21425. doi: 10.1021/acsomega.4c01752. eCollection 2024 May 14.
As a critical mitotic regulator, Aurora kinase A (AURKA) is aberrantly activated in a wide range of cancers. Therapeutic targeting of AUKRA is a promising strategy for the treatment of solid tumors. In this study, we evaluated the preclinical characteristics of JAB-2485, a small-molecule inhibitor of AURKA currently in Phase I/IIa clinical trial in the US (NCT05490472). Biochemical studies demonstrated that JAB-2485 is potent and highly selective on AURKA, with subnanomolar IC and around 1500-fold selectivity over AURKB or AURKC. In addition, JAB-2485 exhibited favorable pharmacokinetic properties featured by low clearance and good bioavailability, strong dose-response relationship, as well as low risk for hematotoxicity and off-target liability. As a single agent, JAB-2485 effectively induced G2/M cell cycle arrest and apoptosis and inhibited the proliferation of small cell lung cancer, triple-negative breast cancer, and neuroblastoma cells. Furthermore, JAB-2485 exhibited robust antitumor activity both as monotherapy and in combination with chemotherapies or the bromodomain inhibitor JAB-8263 in xenograft models of various cancer types. Together, these encouraging preclinical data provide a strong basis for safety and efficacy evaluations of JAB-2485 in the clinical setting.
作为一种关键的有丝分裂调节因子，极光激酶A（AURKA）在多种癌症中被异常激活。靶向AURKA进行治疗是一种很有前景的实体瘤治疗策略。在本研究中，我们评估了JAB-2485的临床前特性，它是一种AURKA小分子抑制剂，目前正在美国进行I/IIa期临床试验（NCT05490472）。生化研究表明，JAB-2485对AURKA具有强效且高度选择性，其半数抑制浓度（IC）低于纳摩尔级别，对AURKB或AURKC的选择性约为1500倍。此外，JAB-2485表现出良好的药代动力学特性，特点是清除率低、生物利用度好、剂量反应关系强，以及血液毒性和脱靶风险低。作为单一药物，JAB-2485有效诱导G2/M期细胞周期阻滞和凋亡，并抑制小细胞肺癌、三阴性乳腺癌和神经母细胞瘤细胞的增殖。此外，在各种癌症类型的异种移植模型中，JAB-2485作为单一疗法以及与化疗或溴结构域抑制剂JAB-8263联合使用时均表现出强大的抗肿瘤活性。总之，这些令人鼓舞的临床前数据为JAB-2485在临床环境中的安全性和疗效评估提供了有力依据。
