Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors
Abstract Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03269-0 |
| _version_ | 1819158145614741504 |
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| author | Christoph Grohmann Francesca Walker Mark Devlin Meng-Xiao Luo Anderly C. Chüeh Judy Doherty François Vaillant Gwo-Yaw Ho Matthew J. Wakefield Clare E. Weeden Alvin Kamili Jayne Murray Sela T. Po’uha Janet Weinstock Serena R. Kane Maree C. Faux Esmee Broekhuizen Ye Zheng Kristy Shield-Artin Nadia J. Kershaw Chin Wee Tan Helen M. Witchard Gregor Ebert Susan A. Charman Ian Street Maria Kavallaris Michelle Haber Jamie I. Fletcher Marie-Liesse Asselin-Labat Clare L. Scott Jane E. Visvader Geoffrey J. Lindeman Keith G. Watson Antony W. Burgess Guillaume Lessene |
| author_facet | Christoph Grohmann Francesca Walker Mark Devlin Meng-Xiao Luo Anderly C. Chüeh Judy Doherty François Vaillant Gwo-Yaw Ho Matthew J. Wakefield Clare E. Weeden Alvin Kamili Jayne Murray Sela T. Po’uha Janet Weinstock Serena R. Kane Maree C. Faux Esmee Broekhuizen Ye Zheng Kristy Shield-Artin Nadia J. Kershaw Chin Wee Tan Helen M. Witchard Gregor Ebert Susan A. Charman Ian Street Maria Kavallaris Michelle Haber Jamie I. Fletcher Marie-Liesse Asselin-Labat Clare L. Scott Jane E. Visvader Geoffrey J. Lindeman Keith G. Watson Antony W. Burgess Guillaume Lessene |
| author_sort | Christoph Grohmann |
| collection | DOAJ |
| description | Abstract Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers. |
| first_indexed | 2024-12-22T16:20:00Z |
| format | Article |
| id | doaj.art-041aa5232fd84ed8be1a33555359e8d7 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-22T16:20:00Z |
| publishDate | 2021-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-041aa5232fd84ed8be1a33555359e8d72022-12-21T18:20:15ZengNature Publishing GroupCell Death and Disease2041-48892021-03-0112311810.1038/s41419-020-03269-0Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumorsChristoph Grohmann0Francesca Walker1Mark Devlin2Meng-Xiao Luo3Anderly C. Chüeh4Judy Doherty5François Vaillant6Gwo-Yaw Ho7Matthew J. Wakefield8Clare E. Weeden9Alvin Kamili10Jayne Murray11Sela T. Po’uha12Janet Weinstock13Serena R. Kane14Maree C. Faux15Esmee Broekhuizen16Ye Zheng17Kristy Shield-Artin18Nadia J. Kershaw19Chin Wee Tan20Helen M. Witchard21Gregor Ebert22Susan A. Charman23Ian Street24Maria Kavallaris25Michelle Haber26Jamie I. Fletcher27Marie-Liesse Asselin-Labat28Clare L. Scott29Jane E. Visvader30Geoffrey J. Lindeman31Keith G. Watson32Antony W. Burgess33Guillaume Lessene34Walter and Eliza Hall InstituteWalter and Eliza Hall InstitutePeter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre buildingWalter and Eliza Hall InstituteWalter and Eliza Hall InstitutePeter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre buildingWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSWChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSWChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSWWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash UniversityWalter and Eliza Hall InstituteChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSWChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSWChildren’s Cancer Institute, Lowy Cancer Research Centre, UNSWWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteWalter and Eliza Hall InstituteAbstract Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.https://doi.org/10.1038/s41419-020-03269-0 |
| spellingShingle | Christoph Grohmann Francesca Walker Mark Devlin Meng-Xiao Luo Anderly C. Chüeh Judy Doherty François Vaillant Gwo-Yaw Ho Matthew J. Wakefield Clare E. Weeden Alvin Kamili Jayne Murray Sela T. Po’uha Janet Weinstock Serena R. Kane Maree C. Faux Esmee Broekhuizen Ye Zheng Kristy Shield-Artin Nadia J. Kershaw Chin Wee Tan Helen M. Witchard Gregor Ebert Susan A. Charman Ian Street Maria Kavallaris Michelle Haber Jamie I. Fletcher Marie-Liesse Asselin-Labat Clare L. Scott Jane E. Visvader Geoffrey J. Lindeman Keith G. Watson Antony W. Burgess Guillaume Lessene Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors Cell Death and Disease |
| title | Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors |
| title_full | Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors |
| title_fullStr | Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors |
| title_full_unstemmed | Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors |
| title_short | Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors |
| title_sort | preclinical small molecule wehi 7326 overcomes drug resistance and elicits response in patient derived xenograft models of human treatment refractory tumors |
| url | https://doi.org/10.1038/s41419-020-03269-0 |
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