방사선의학 웹진

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Abstract
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.

Affiliations

Hanna Cho  1 , Injae Shin  1   2 , Hojong Yoon  3 , Eunhye Jeon  1 , Jiwon Lee  1 , Younghoon Kim  1   2 , SeongShick Ryu  1   2 , Chiman Song  3 , Nam Hoon Kwon  4   5 , Youngji Moon  4 , Sunghoon Kim  4   5 , Nam Doo Kim  6 , Hwan Geun Choi  3   7 , Taebo Sim  1   2   3
1 Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
2 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
3 Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
4 Medicinal Bioconvergence Research Center, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
5 Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
6 Voronoibio Inc., 32 Songdogwahak-ro, Yeonsu-gu, Incheon 21984, Republic of Korea.
7 B2Sbio Inc., 32 Songdogwahak-ro, Yeonsu-gu, Incheon 21984, Republic of Korea.