Design, synthesis, and evaluation of purine and pyrimidine-based KRAS G12D inhibitors: Towards potential anticancer therapy.

Autor:	Park SY; College of Pharmacy and Drug Information Research Institute, Sookmyung Women's University, 100 Cheongpa-ro 47-gil, Yongsan-gu, Seoul, 04310, Republic of Korea., Gowda Saralamma VV; Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-Ro, Gangnam-Gu, Seoul 06273, Republic of Korea., Nale SD; BNJBiopharma, 2nd Floor Memorial Hall, 85, Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea., Kim CJ; Department of Biotechnology, Graduate School, The Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Republic of Korea., Jo YS; Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-Ro, Gangnam-Gu, Seoul 06273, Republic of Korea., Baig MH; Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-Ro, Gangnam-Gu, Seoul 06273, Republic of Korea., Cho J; College of Pharmacy and Drug Information Research Institute, Sookmyung Women's University, 100 Cheongpa-ro 47-gil, Yongsan-gu, Seoul, 04310, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Heliyon [Heliyon] 2024 Apr 02; Vol. 10 (7), pp. e28495. Date of Electronic Publication: 2024 Apr 02 (Print Publication: 2024).
DOI:	10.1016/j.heliyon.2024.e28495
Abstrakt:	Oncogenic RAS mutations, commonly observed in human tumors, affect approximately 30% of cancer cases and pose a significant challenge for effective cancer treatment. Current strategies to inhibit the KRAS G12D mutation have shown limited success, emphasizing the urgent need for new therapeutic approaches. In this study, we designed and synthesized several purine and pyrimidine analogs as inhibitors for the KRAS G12D mutation. Our synthesized compounds demonstrated potent anticancer activity against cell lines with the KRAS G12D mutation, effectively impeding their growth. They also exhibited low toxicity in normal cells, indicating their selective action against cancer cells harboring the KRAS G12D mutation. Notably, the lead compound, PU1-1 induced the programmed cell death of KRAS G12D-mutated cells and reduced the levels of active KRAS and its downstream signaling proteins. Moreover, PU1-1 significantly shrunk the tumor size in a pancreatic xenograft model induced by the KRAS G12D mutation, further validating its potential as a therapeutic agent. These findings highlight the potential of purine-based KRAS G12D inhibitors as candidates for targeted cancer therapy. However, further exploration and optimization of these compounds are essential to meet the unmet clinical needs of patients with KRAS -mutant cancers. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2024 Published by Elsevier Ltd.)
Databáze:	MEDLINE
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