A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins
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 chemotherap...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/13/5226 |
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| author | Snehal Nirgude Shahana M. V. Febina Ravindran Sujeet Kumar Shivangi Sharma Raghunandan Mahadeva Anisha Mhatre Subhas S. Karki Bibha Choudhary |
| author_facet | Snehal Nirgude Shahana M. V. Febina Ravindran Sujeet Kumar Shivangi Sharma Raghunandan Mahadeva Anisha Mhatre Subhas S. Karki Bibha Choudhary |
| author_sort | Snehal Nirgude |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T01:33:09Z |
| format | Article |
| id | doaj.art-49a6da36f66247a29386de550b4f12b6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T01:33:09Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-49a6da36f66247a29386de550b4f12b62023-11-18T17:10:05ZengMDPI AGMolecules1420-30492023-07-012813522610.3390/molecules28135226A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client ProteinsSnehal Nirgude0Shahana M. V.1Febina Ravindran2Sujeet Kumar3Shivangi Sharma4Raghunandan Mahadeva5Anisha Mhatre6Subhas S. Karki7Bibha Choudhary8Institute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore 560100, Karnataka, IndiaInstitute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore 560100, Karnataka, IndiaInstitute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore 560100, Karnataka, IndiaDr. Prabhakar B. Kore Basic Science Research Laboratory Center (Off-Campus), Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Rajajinagar, (A Constituent Unit of KLE Academy of Higher Education; Research, Belagavi), Bangalore 560010, Karnataka, IndiaInstitute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore 560100, Karnataka, IndiaInstitute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore 560100, Karnataka, IndiaInstitute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore 560100, Karnataka, IndiaDr. Prabhakar B. Kore Basic Science Research Laboratory Center (Off-Campus), Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Rajajinagar, (A Constituent Unit of KLE Academy of Higher Education; Research, Belagavi), Bangalore 560010, Karnataka, IndiaInstitute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore 560100, Karnataka, IndiaDespite 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.https://www.mdpi.com/1420-3049/28/13/5226HSP90 inhibitorDLA mouse tumor modelapoptosisanticancer therapeutics |
| spellingShingle | Snehal Nirgude Shahana M. V. Febina Ravindran Sujeet Kumar Shivangi Sharma Raghunandan Mahadeva Anisha Mhatre Subhas S. Karki Bibha Choudhary A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins Molecules HSP90 inhibitor DLA mouse tumor model apoptosis anticancer therapeutics |
| title | A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins |
| title_full | A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins |
| title_fullStr | A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins |
| title_full_unstemmed | A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins |
| title_short | A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins |
| title_sort | coumarin imidazothiadiazole derivative sp11 abrogates tumor growth by targeting hsp90 and its client proteins |
| topic | HSP90 inhibitor DLA mouse tumor model apoptosis anticancer therapeutics |
| url | https://www.mdpi.com/1420-3049/28/13/5226 |
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