Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity

Beijing Chen; Mingyang Sun; Chun Zhang; Qi Huang; Dan Teng; Linghao Hu; Huicong Ma; Xinyi Lin; Zan Huang; Renzhao Gui; Xiaobei Hu; Lei Xu; Mingyue Zheng; Yubo Zhou; Jia Li; Mingliang Wang

doi:10.1021/acs.jmedchem.4c01605

Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity

J Med Chem. 2024 Nov 22. doi: 10.1021/acs.jmedchem.4c01605. Online ahead of print.

Authors

Beijing Chen^{1

2}, Mingyang Sun¹, Chun Zhang^{1

3}, Qi Huang^{1

4}, Dan Teng⁵, Linghao Hu^{1

6}, Huicong Ma^{1

3}, Xinyi Lin^{1

7}, Zan Huang¹, Renzhao Gui¹, Xiaobei Hu¹, Lei Xu¹, Mingyue Zheng⁵, Yubo Zhou^{1

8}, Jia Li^{1

8

9

2}, Mingliang Wang^{1

6

3}

Affiliations

¹ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Tsuihang New District, Zhongshan 528400, Guangdong, China.
² School of Pharmacy, Guizhou Medical University, Guiyang 550014, China.
³ School of Pharmacy, Zunyi Medical University, Zunyi 563000, China.
⁴ School of Pharmacy, Fudan University, Shanghai 201203, China.
⁵ Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁶ Department of Medicinal Chemistry, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁷ School of Pharmaceutical Sciences, Southern Medical University, No. 1023 South Shatai Road Baiyun District, Guangzhou 510515, Guangdong, China.
⁸ State Key Laboratory of Drug Research, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁹ State Key Laboratory of Chemical Biology, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.

PMID: 39574384
DOI: 10.1021/acs.jmedchem.4c01605

Abstract

Human sapiens caseinolytic protease P (ClpP) is essential for maintaining mitochondrial proteome homeostasis, and its activation is increasingly recognized as a promising cancer therapy strategy. Herein, based on structure-guided drug design, we discovered a series of potent ClpP activators by introducing a methyl group to the imipridone scaffold of the ClpP activator ONC201 in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, CLPP-1071, exhibited exceptionally potent ClpP agonistic activity (EC₅₀ = 23.5 nM, 107.1-fold stronger than ONC201) and inhibited the proliferation of HL60 cells (IC₅₀ = 4.6 nM, 169.2-fold stronger than ONC201). CLPP-1071 possesses good pharmacokinetic properties and effectively prolongs the lifespan in the MOLM13 and HL60 xenograft models in mice through oral administration. CLPP-1071 is the most potent and orally efficacious ClpP activator reported to date.