Identification of non-ATP-competitive α-carboline inhibitors of the anaplastic lymphoma kinase.
| Title: | Identification of non-ATP-competitive α-carboline inhibitors of the anaplastic lymphoma kinase. |
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| Authors: | Mologni L; Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Galkem Srl, Monza, Italy. Electronic address: luca.mologni@unimib.it.; Orsato A; Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France; Dept. of Chemistry, Universidade Estadual de Londrina, Paraná, Brazil.; Zambon A; Department of Chemistry and Geological Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Tardy S; Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France; School of Pharmaceutical Sciences, University of Geneva, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Switzerland.; Bisson WH; School of Pharmaceutical Sciences, University of Geneva, Switzerland; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.; Schneider C; Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France.; Ceccon M; Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.; Viltadi M; Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.; D'Attoma J; Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France.; Pannilunghi S; School of Pharmaceutical Sciences, University of Geneva, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Switzerland.; Vece V; Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.; Gueyrard D; Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France.; Bertho J; Galkem Srl, Monza, Italy.; Scapozza L; Galkem Srl, Monza, Italy; School of Pharmaceutical Sciences, University of Geneva, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Switzerland. Electronic address: leonardo.scapozza@unige.ch.; Goekjian P; Galkem Srl, Monza, Italy; Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France.; Gambacorti-Passerini C; Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Galkem Srl, Monza, Italy. |
| Source: | European journal of medicinal chemistry [Eur J Med Chem] 2022 Aug 05; Vol. 238, pp. 114488. Date of Electronic Publication: 2022 May 25. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Paris : Editions Scientifiques Elsevier; Original Publication: Paris, S.E.C.T. [etc.] |
| MeSH Terms: | Carbolines*/pharmacology ; Receptor Protein-Tyrosine Kinases*; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Anaplastic Lymphoma Kinase ; Animals ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Humans ; Mice ; Mutation |
| Abstract: | The Anaplastic Lymphoma Kinase (ALK) is a therapeutic target for personalized medicine in selected cancers. Despite excellent clinical responses to ALK inhibitors, most patients develop drug resistance and relapse. New compounds with alternative binding modes are needed to overcome resistant mutants. Here we describe a medicinal chemistry effort to the design and development of novel ALK inhibitors based on a 4,6-substituted α-carboline scaffold. Active compounds were able to inhibit the gatekeeper L1196M mutant, in several cases better than the wild-type enzyme. Compound 43 showed potent non-ATP-competitive inhibition of wild-type and mutant ALK, including G1202R, in biochemical and cellular assays, as well as in xenograft mouse models.; (Copyright © 2022 Elsevier Masson SAS. All rights reserved.) |
| Contributed Indexing: | Keywords: ALCL; ALK; Drug resistance; Gatekeeper; Non-competitive |
| Substance Nomenclature: | 0 (Carbolines); 0 (Protein Kinase Inhibitors); 244-76-8 (alpha-carboline); EC 2.7.10.1 (Anaplastic Lymphoma Kinase); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) |
| Entry Date(s): | Date Created: 20220606 Date Completed: 20220623 Latest Revision: 20220623 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.ejmech.2022.114488 |
| PMID: | 35665691 |
| Database: | MEDLINE |
Journal Article