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A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.

التفاصيل البيبلوغرافية
العنوان: A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.
المؤلفون: Whitehead CE; Department of Radiology, University of Michigan, Ann Arbor, MI, USA.; MEKanistic Therapeutics, Inc., Ann Arbor, MI, USA., Ziemke EK; Department of Radiology, University of Michigan, Ann Arbor, MI, USA., Frankowski-McGregor CL; Department of Radiology, University of Michigan, Ann Arbor, MI, USA., Mumby RA; Department of Radiology, University of Michigan, Ann Arbor, MI, USA., Chung J; Department of Radiology, University of Michigan, Ann Arbor, MI, USA., Li J; Department of Biostatistics, The University of Michigan School of Public Health, Ann Arbor, MI, USA., Osher N; Department of Biostatistics, The University of Michigan School of Public Health, Ann Arbor, MI, USA., Coker O; The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Baladandayuthapani V; Department of Biostatistics, The University of Michigan School of Public Health, Ann Arbor, MI, USA.; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., Kopetz S; The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sebolt-Leopold JS; Department of Radiology, University of Michigan, Ann Arbor, MI, USA. jssl@med.umich.edu.; MEKanistic Therapeutics, Inc., Ann Arbor, MI, USA. jssl@med.umich.edu.; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. jssl@med.umich.edu.; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. jssl@med.umich.edu.
المصدر: Nature cancer [Nat Cancer] 2024 Jul 11. Date of Electronic Publication: 2024 Jul 11.
Publication Model: Ahead of Print
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101761119 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2662-1347 (Electronic) Linking ISSN: 26621347 NLM ISO Abbreviation: Nat Cancer Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Publishing Group, [2020]-
مستخلص: Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.
(© 2024. The Author(s).)
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معلومات مُعتمدة: R41 CA261407 United States CA NCI NIH HHS; R44 CA213715, R41 CA261407 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); R01 CA220199, R01 CA241764, R21 CA267412, R44 CA213715, R41 CA261407, P30 CA046592 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); R21 CA267412 United States CA NCI NIH HHS; R44 CA213715 United States CA NCI NIH HHS; R01 CA220199 United States CA NCI NIH HHS; R01 CA241764 United States CA NCI NIH HHS
تواريخ الأحداث: Date Created: 20240711 Latest Revision: 20240814
رمز التحديث: 20240815
DOI: 10.1038/s43018-024-00781-6
PMID: 38992135
قاعدة البيانات: MEDLINE
الوصف
تدمد:2662-1347
DOI:10.1038/s43018-024-00781-6