Discovery of novel heat shock protein (Hsp90) inhibitors based on luminespib with potent antitumor activity |
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| Institution: | 1. Research Laboratories, Ildong Pharmaceutical Co., Hwaseong-si, Gyeonggi-do 18449, South Korea;2. AIMS BioScience Co., 2, Baumoe-ro 27-gil, Seocho-gu, Seoul 06752, South Korea;3. Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, South Korea;1. Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Bachupally, Kukatpally, Hyderabad 500090, India;2. Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad 500042, India;3. Department of Chemistry, University College of Science and Faculty of Pharmacy, Osmania University, Hyderabad 500007, India;1. School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China;2. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China;3. Anticancer Agent Research Center, KRIBB, Cheongju 28116, Republic of Korea;1. National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune, 411007, India;2. Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, 835215, India;3. Centre for DNA Fingerprinting and Diagnostics, Hyderabad, 500039, India;1. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore;2. School of Biological Sciences, Nanyang Technological University (NTU), Singapore 637551, Singapore |
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| Abstract: | A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 inhibition in ATPase activity and Her2 degradation assays and significant antitumor activity in A2780 and HCT116 cell lines. Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket. |
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| Keywords: | Heat shock protein 90 Luminespib Antitumor agent |
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