Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy
Zhimin Zhang, Liubin Guo, Mengting Zhao, Hao Pan, Dong Zhao, Lingling Wang, Xi Yang, Zhiping Zhang, Mengqiang Wu, Yujie Chang, Yacheng Yang, Linan Sun, Sirui Liu, Rongyao Zhu, Haowen Zheng, Xinyu Dai, Xiaohua Zhang, Chunhua Jiang, Zhuangzhi Zhu, Yuchen Zhang, Dongzhou Liu
Abstract
Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as a negative immune regulator of T-cell receptor signaling. Deprivation of the HPK1 function suppresses tumor growth, providing an attractive strategy for cancer immunotherapy. Herein, we present a novel PROTAC-based HPK1 degrader compound DD205-291 with high selectivity and potency. DD205-291 showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, DD205-291 exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of DD205-291 at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, DD205-291 exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that DD205-291 is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.