Identification of non-ATP-competitive α-carboline inhibitors of the anaplastic lymphoma kinase

Luca Mologni; Alexandre Orsato; Alfonso Zambon; Sébastien Tardy; William H Bisson; Cedric Schneider; Monica Ceccon; Michela Viltadi; Joseph D'Attoma; Sara Pannilunghi; Vito Vece; David Gueyrard; Jerome Bertho; Leonardo Scapozza; Peter Goekjian; Carlo Gambacorti-Passerini

doi:10.1016/j.ejmech.2022.114488

Identification of non-ATP-competitive α-carboline inhibitors of the anaplastic lymphoma kinase

Eur J Med Chem. 2022 Aug 5:238:114488. doi: 10.1016/j.ejmech.2022.114488. Epub 2022 May 25.

Authors

Luca Mologni¹, Alexandre Orsato², Alfonso Zambon³, Sébastien Tardy⁴, William H Bisson⁵, Cedric Schneider⁶, Monica Ceccon⁷, Michela Viltadi⁷, Joseph D'Attoma⁶, Sara Pannilunghi⁸, Vito Vece⁹, David Gueyrard⁶, Jerome Bertho¹⁰, Leonardo Scapozza¹¹, Peter Goekjian¹², Carlo Gambacorti-Passerini¹³

Affiliations

¹ Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Galkem Srl, Monza, Italy. Electronic address: luca.mologni@unimib.it.
² Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France; Dept. of Chemistry, Universidade Estadual de Londrina, Paraná, Brazil.
³ Department of Chemistry and Geological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
⁴ 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.
⁵ School of Pharmaceutical Sciences, University of Geneva, Switzerland; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁶ Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France.
⁷ Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
⁸ School of Pharmaceutical Sciences, University of Geneva, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Switzerland.
⁹ Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Galkem Srl, Monza, Italy.
¹¹ 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.
¹² Galkem Srl, Monza, Italy; Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Villeurbanne, France.
¹³ Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Galkem Srl, Monza, Italy.

PMID: 35665691
DOI: 10.1016/j.ejmech.2022.114488

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.

Keywords: ALCL; ALK; Drug resistance; Gatekeeper; Non-competitive.

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Carbolines* / pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Mice
Mutation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Receptor Protein-Tyrosine Kinases*

Substances

Carbolines
Protein Kinase Inhibitors
alpha-carboline
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases