Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases,Journal of Medicinal Chemistry

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Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-12 , DOI: 10.1021/acs.jmedchem.3c02046
Lushun Wang ₁ , Monica J Bohmer ₂ , Jinhua Wang _{3,

4} , Flore Nardella ₂ , Jaeson Calla ₅ , Mariana Laureano De Souza ₅ , Kyra A Schindler ₆ , Lukas Montejo ₂ , Nimisha Mittal ₅ , Frances Rocamora ₅ , Mayland Treat ₇ , Jordan T Charlton ₈ , Patrick K Tumwebaze ₉ , Philip J Rosenthal ₁₀ , Roland A Cooper ₈ , Ratna Chakrabarti ₁₁ , Elizabeth A Winzeler ₅ , Debopam Chakrabarti ₂ , Nathanael S Gray ₁

Affiliation

Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States.
Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
Department of Pediatrics, School of Medicine, University California, San Diego, La Jolla, California 92093, United States.
Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
School of Public Health, University of California, Berkeley California 94704, United States.
Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California 94901, United States.
Infectious Disease Research Collaboration, Kampala, Uganda.
Department of Medicine, University of California, San Francisco, California 94110, United States.
Division of Cancer Research, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.

While progress has been made in the effort to eradicate malaria, the disease remains a significant threat to global health. Acquired resistance to frontline treatments is emerging in Africa, urging a need for the development of novel antimalarial agents. Repurposing human kinase inhibitors provides a potential expedited route given the availability of a diverse array of kinase-targeting drugs that are approved or in clinical trials. Phenotypic screening of a library of type II human kinase inhibitors identified compound 1 as a lead antimalarial, which was initially developed to target human ephrin type A receptor 2 (EphA2). Here, we report a structure–activity relationship study and lead optimization of compound 1, which led to compound 33, with improved antimalarial activity and selectivity.

中文翻译：

发现比人类激酶具有选择性的强效抗疟 II 型激酶抑制剂

尽管根除疟疾的努力取得了进展，但该疾病仍然对全球健康构成重大威胁。非洲正在出现对一线治疗的获得性耐药，这迫切需要开发新型抗疟药物。鉴于已批准或正在进行临床试验的多种激酶靶向药物的可用性，重新利用人类激酶抑制剂提供了一条潜在的快速途径。对 II 型人类激酶抑制剂库的表型筛选将化合物1鉴定为一种主要抗疟药，该药物最初是针对人类肝配蛋白 A 型受体 2 (EphA2) 开发的。在这里，我们报告了化合物1的构效关系研究和先导化合物优化，最终得到了具有改善的抗疟活性和选择性的化合物33 。

更新日期：2024-01-12

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