Identification of Thieno[3,2- d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3

Hanna Cho, Injae Shin, Hojong Yoon, Eunhye Jeon, Jiwon Lee, Younghoon Kim, Seongshick Ryu, Chiman Song, Nam Hoon Kwon, Youngji Moon, Sunghoon Kim, Nam Doo Kim, Hwan Geun Choi, Taebo Sim

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8 Citations (Scopus)


Focal adhesion kinase (FAK) is overexpressed in highly invasive and metastatic cancers. To identify novel FAK inhibitors, we designed and synthesized various thieno[3,2-d]pyrimidine derivatives. An intensive structure-activity relationship (SAR) study led to the identification of 26 as a lead. Moreover, 26, a multitargeted kinase inhibitor, possesses excellent potencies against FLT3 mutants as well as FAK. Gratifyingly, 26 remarkably inhibits recalcitrant FLT3 mutants, including F691L, that cause drug resistance. Importantly, 26 is superior to PF-562271 in terms of apoptosis induction, anchorage-independent growth inhibition, and tumor burden reduction in the MDA-MB-231 xenograft mouse model. Also, 26 causes regression of tumor growth in the MV4-11 xenograft mouse model, indicating that it could be effective against acute myeloid leukemia (AML). Finally, in an orthotopic mouse model using MDA-MB-231, 26 remarkably prevents metastasis of orthotopic tumors to lymph nodes. Taken together, the results indicate that 26 possesses potential therapeutic value against highly invasive cancers and relapsed AML.

Original languageEnglish
Pages (from-to)11934-11957
Number of pages24
JournalJournal of Medicinal Chemistry
Issue number16
Publication statusPublished - 2021 Aug 26

Bibliographical note

Funding Information:
This study was financially supported by the Candidate Development Program (NRF2016M3A9B5940991) and NRF-2021R1A2C3011992/NRF-M3A6A4-2010-0029785/NRF-2015M3A6A4065724 from the National Research Foundation in Korea, Korea Institute of Science and Technology (KIST), Brain Korea 21 Project, and the KU-KIST Graduate School of Converging Science and Technology Program.

Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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