The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance
العنوان: | The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance |
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المؤلفون: | Leah Fung, Hans C. Lee, Richard J. Jones, Frank Mercurio, Robert W. Sullivan, Imelda Lam, David I. Stirling, Fazal Shirazi, Jianxuan Zou, Paul Erdman, David Hecht, Hua Wang, Normand Richard, Kyle W. H. Chan, Brooke McElwee, Aparajita Hoskote Chourasia, Elisabet E. Manasanch, Isere Kuiatse, Robert Z. Orlowski, Eduardo Torres |
المصدر: | Journal of Molecular Medicine. 98:1161-1173 |
بيانات النشر: | Springer Science and Business Media LLC, 2020. |
سنة النشر: | 2020 |
مصطلحات موضوعية: | Ubiquitin-Protein Ligases, Antineoplastic Agents, Apoptosis, Bortezomib, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Cell Line, Tumor, hemic and lymphatic diseases, Drug Discovery, Biomarkers, Tumor, medicine, Animals, Humans, Lenalidomide, Genetics (clinical), Multiple myeloma, Dexamethasone, Cell Proliferation, Chemistry, Cereblon, medicine.disease, Pomalidomide, Thalidomide, Disease Models, Animal, Drug Resistance, Neoplasm, Proteostasis, Cancer research, Molecular Medicine, Multiple Myeloma, 030215 immunology, medicine.drug |
الوصف: | Small molecules targeting the cereblon-containing E3 ubiquitin ligase including thalidomide, lenalidomide, and pomalidomide modulate turnover of downstream client proteins and demonstrate pre-clinical and clinical anti-myeloma activity. Different drugs that engage with cereblon hold the potential of unique phenotypic effects, and we therefore studied the novel protein homeostatic modulator (PHM™) BTX306 with a unique thiophene-fused scaffold bearing a substituted phenylurea and glutarimide. This agent much more potently reduced human-derived myeloma cell line viability, with median inhibitory concentrations in the single nanomolar range versus micromolar values for lenalidomide or pomalidomide, and more potently activated caspases 3/8/9. While lenalidomide and pomalidomide induced greater degradation of Ikaros and Aiolos in myeloma cells, BTX306 more potently reduced levels of GSPT1, eRF1, CK1α, MCL-1, and c-MYC. Suppression of cereblon or overexpression of Aiolos or Ikaros induced relative resistance to BTX306, and this agent did not impact viability of murine hematopoietic cells in an in vivo model, demonstrating its specificity for human cereblon. Interestingly, BTX306 did show some reduced activity in lenalidomide-resistant cell line models but nonetheless retained its nanomolar potency in vitro, overcame bortezomib resistance, and was equipotent against otherwise isogenic cell line models with either wild-type or knockout TP53. Finally, BTX306 demonstrated strong activity against primary CD138-positive plasma cells, showed enhanced anti-proliferative activity in combination with bortezomib and dexamethasone, and was effective in an in vivo systemic model of multiple myeloma. Taken together, the data support further translational studies of BTX306 and its derivatives to the clinic for patients with relapsed and/or refractory myeloma. KEY MESSAGES: BTX306 has a unique thiophene-fused scaffold bearing phenylurea and glutarimide. BTX306 is more potent against myeloma cells than lenalidomide or pomalidomide. BTX306 overcomes myeloma cell resistance to lenalidomide or bortezomib in vitro. BTX306 is active against primary myeloma cells, and shows efficacy in vivo. |
تدمد: | 1432-1440 0946-2716 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e06af628a339051f75823cfd26ea68ed https://doi.org/10.1007/s00109-020-01943-6 |
حقوق: | CLOSED |
رقم الأكسشن: | edsair.doi.dedup.....e06af628a339051f75823cfd26ea68ed |
قاعدة البيانات: | OpenAIRE |
تدمد: | 14321440 09462716 |
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