2. Academic Validation
  3. Designing Macrocyclic Kinase Inhibitors Using Macrocycle Scaffold Hopping with Reinforced Learning (Macro-Hop)

Designing Macrocyclic Kinase Inhibitors Using Macrocycle Scaffold Hopping with Reinforced Learning (Macro-Hop)

  • J Med Chem. 2025 Mar 27;68(6):6698-6717. doi: 10.1021/acs.jmedchem.5c00087.
Hong Liang 1,  Shengjie Huang 1,  Xinxin Xu 1,  Zhao Yin 2,  Muzammal Hussain 3,  Xiaojuan Song 1,  Jianqiao Yi 1,  Yingqi He 1,  Jing Guo 1,  Zhengchao Tu 1,  Zhang Zhang 1,  Yang Zhou 1,  Xiaoyun Lu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 2 Department of Hematology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong Province 510317, China.
  • 3 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, New York 10016, United States.
PMID: 40101196 DOI: 10.1021/acs.jmedchem.5c00087
Abstract

Macrocycles have gained significant attention in drug discovery, with over 70 macrocyclic compounds currently in clinical use. Despite this progress, the effective methods for designing macrocycles remain elusive. In this study, we present Macro-Hop, a reinforced learning framework designed to rapidly and comprehensively explore the macrocycle chemical space. Macro-Hop efficiently generates novel macrocyclic scaffolds that not only align with predefined physicochemical properties but also exhibit 3D structural similarities to a specified reference compound. As a proof of concept, we applied Macro-Hop to design a new series of macrocycle inhibitors targeting PDGFRαD842 V kinase. The representative compound L7 exhibited high potency against PDGFRαD842 V in both biochemical and cellular assays with IC50 values of 23.8 and 2.1 nM, respectively. L7 effectively inhibited clinically relevant secondary mutants PDGFRαD842 V/G680R (IC50 = 64.1 nM) and PDGFRαD842 V/T674I (IC50 = 27.6 nM), highlighting the rapid effectiveness of wet-leb validation with Macro-Hop.

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