2. Academic Validation
  3. Design, Synthesis, and Pharmacological Evaluation of Multisubstituted Pyrido[4,3- d]pyrimidine Analogues Bearing Deuterated Methylene Linkers as Potent KRASG12D Inhibitors

Design, Synthesis, and Pharmacological Evaluation of Multisubstituted Pyrido[4,3- d]pyrimidine Analogues Bearing Deuterated Methylene Linkers as Potent KRASG12D Inhibitors

  • J Med Chem. 2023 Nov 3. doi: 10.1021/acs.jmedchem.3c01724.
Xuanzheng Xiao 1 2,  Juanjuan Feng 3,  Jing Ma 1,  Xinting Xia 3,  Xiaogu Liu 4,  Jian Zhang 1 5,  Chunyong Ding 1 2,  Xiufeng Pang 3,  Ao Zhang 1 5 2 6
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 4 Southern Medical University Affiliated Fengxian Hospital, The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
  • 5 Lingang Laboratory, Shanghai 200210,China.
  • 6 National Key Laboratory of Innovative Immunotherapy, Shanghai 200240, China.
PMID: 37921024 DOI: 10.1021/acs.jmedchem.3c01724
Abstract

The breakthrough in drug development of KRASG12C inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRASG12D variant. Based on the structural analysis of MRTX1133 in complex with KRASG12D, a comprehensive structure-activity study was conducted, which led to the discovery of several compounds (22, 28, and 31) that showed higher potency in suppressing the clonogenic growth of KRASG12D-dependent Cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRASG12D with IC50 values between 0.48 and 1.21 nM. These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high in vitro and in vivo potency of these new inhibitors call for further profiling.

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