Rational Design of a Novel 6 H-Benzo[ c]chromen Series as Selective PI3Kα Inhibitors

  • J Med Chem. 2024 Sep 12;67(17):15387-15410. doi: 10.1021/acs.jmedchem.4c00992.
Xue Shi  1 ,  Heng Feng  2 ,  Haigang Tian  2 ,  Haibiao Ma  2 ,  Xiaomeng Pang  2 ,  Chenhan Mao  2 ,  Peng Xiang  2 ,  Zhengze Xu  2 ,  Weidong Han  2 ,  Yuxiang Yan  2 ,  Wei Chen  2 ,  Yuqing Nan  2 ,  Guanjun Nan  3 ,  Zhenyue Hu  1 ,  Lingyun Hui  4 ,  Chenglong Li  5 ,  Yiping Li  2
Affiliations
  • 1. Biobank, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
  • 3. Department of Pharmaceutical Analysis, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
  • 4. Clinical Laboratory Center, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
  • 5. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
PMID: 39159497 DOI: 10.1021/acs.jmedchem.4c00992
Abstract

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human Cancer, and PI3Kα is one of the most frequently mutated kinases in human Cancer. A selective PI3Kα Inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a novel series of selective PI3Kα inhibitors using structure-based drug design and molecular docking to inform the design of 6H-benzo[c]chromen inhibitors. XJTU-L453 (21) was identified with PI3Kα inhibitory potency and unique selectivity over Other PI3K isoforms and all Other kinases tested. Further evaluation of pharmacokinetic properties and in vivo efficacy led to the identification of the preclinical potential of XJTU-L453 (21).

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