Abstract 5226: TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors
| Autor: | Vivian Nguyen, Maria Barrera, Wei Deng, Evan Rogers, Xin Zhang, J. Jean Cui, Han Zhang, Dong Lee, Ana Parra, Brion W. Murray, Dayong Zhai, Ung Jane |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Alectinib Cancer Research Mutation Brigatinib Crizotinib Ceritinib medicine.drug_class Chemistry medicine.disease_cause Lorlatinib ALK inhibitor 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology hemic and lymphatic diseases 030220 oncology & carcinogenesis medicine Cancer research Anaplastic lymphoma kinase medicine.drug |
| Zdroj: | Cancer Research. 80:5226-5226 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Anaplastic lymphoma kinase (ALK) gene rearrangements occur in up to 7% of patients with non-small cell lung cancer (NSCLC) with the majority as EML4-ALK fusions. Crizotinib (first generation ALK inhibitor) was the first approved ALK inhibitor for the treatment of ALK-positive metastatic non-small cell lung cancer. However, development of resistance to crizotinib caused by secondary kinase domain mutations, bypass signaling, or morphology changes occurs. Second generation ALK inhibitors alectinib, ceritinib, and brigatinib were able to overcome the majority of ALK resistant mutations (L1196M, G1269A and F1174L) acquired with crizotinib. The solvent front mutation (SFM) G1202R is a common resistant mutation to crizotinib and the second generation ALK inhibitors. Lorlatinib, a third generation ALK inhibitor, can overcome G1202R resistance with moderate IC50 values of 40 - 60 nM in cell-based assays. Although, compound mutations such as ones with both gatekeeper and solvent front mutations (L1196M/G1202R) are refractory to lorlatinib, representing an unmet medical need. TPX-0131 is a next generation ALK inhibitor designed with a compact macrocyclic structure that can bind completely within the ATP binding boundary to overcome a variety of ALK resistant mutations, especially SFM G1202R and compound mutations L1196M/G1202R. TPX-0131 potently inhibits wildtype (WT) ALK and over 20 different ALK mutations with IC50 values 1 μM). Taken together, TPX-0131 is a next generation ALK inhibitor that can overcome a broad spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations (e.g. L1196M/G1202R). The nonclinical pharmacology profile of TPX-0131 warrants further preclinical investigation. Citation Format: J. Jean Cui, Evan Rogers, Dayong Zhai, Wei Deng, Jane Ung, Vivian Nguyen, Han Zhang, Xin Zhang, Ana Parra, Maria Barrera, Dong Lee, Brion Murray. TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5226. |
| Databáze: | OpenAIRE |
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