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A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins

Nirgude, S and V, Shahana M and Ravindran, F and Kumar, S and Sharma, S and Mahadeva, R and Mhatre, A and Karki, SS and Choudhary, B (2023) A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins. In: Molecules, 28 (13).

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Official URL: https://doi.org/10.3390/molecules28135226


Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease’s aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent.

Item Type: Journal Article
Publication: Molecules
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Additional Information: The copyright for this article belongs to the Multidisciplinary Digital Publishing Institute (MDPI)
Keywords: anticancer therapeutics; apoptosis; DLA mouse tumor model; HSP90 inhibitor
Department/Centre: Division of Biological Sciences > Biochemistry
Date Deposited: 01 Aug 2023 05:09
Last Modified: 01 Aug 2023 05:09
URI: https://eprints.iisc.ac.in/id/eprint/82737

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