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

Autor:	Chiman Song, SeongShick Ryu, Nam Doo Kim, Nam Hoon Kwon, Taebo Sim, Injae Shin, Eunhye Jeon, Ji Won Lee, Youngji Moon, Young Hoon Kim, Hojong Yoon, Sunghoon Kim, Hwan Geun Choi, Hanna Cho
Rok vydání:	2021
Předmět:	Kinase Mutant Myeloid leukemia Drug resistance medicine.disease Metastasis Focal adhesion chemistry.chemical_compound chemistry Drug Discovery Fms-Like Tyrosine Kinase 3 Cancer research medicine Molecular Medicine Growth inhibition
Zdroj:	Journal of Medicinal Chemistry. 64:11934-11957
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.1c00459
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::a5deef0a2082593f2759a2669c42e311 https://doi.org/10.1021/acs.jmedchem.1c00459 Zobrazit plný text záznamu