Synthesis and evaluation of 7-azaindole derivatives bearing benzocycloalkanone motifs as protein kinase inhibitors |
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| Affiliation: | 1. Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;2. Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France;3. Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, 29680 Roscoff, France;4. Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA;2. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA;3. Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, USA;4. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA;5. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA;1. School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea;2. Division of Bio & Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea |
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| Abstract: | Protein kinases are important drug targets, especially in the area of oncology. This paper reports the synthesis and biological evaluation of new 7-azaindole derivatives bearing benzocycloalkanone motifs as potential protein kinase inhibitors. Four compounds 8g, 8h, 8i, and 8l were discovered to inhibit cyclin-dependent kinase 9 (CDK9/CyclinT) and/or Haspin kinase in the micromolar to nanomolar range. 8l was identified as the most potent Haspin inhibitor (IC50 = 14 nM), while 8g and 8h acted as dual inhibitors of CDK9/CyclinT and Haspin. These novel compounds constitute a promising starting point for the discovery of dual protein kinase inhibitors that have potential to be developed as anticancer agents, since both CDK9/CyclinT and Haspin are considered to be drug targets in oncology. |
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| Keywords: | 7-azaindole Benzocycloalkanone Protein kinase Structure-activity relationship Haspin CDK9/CyclinT Dual inhibitor Oncology |
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