Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase

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

doi:10.1021/acsomega.2c00507

Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase

ACS Omega. 2022 May 11;7(20):17083-17097. doi: 10.1021/acsomega.2c00507. eCollection 2022 May 24.

Authors

Luca Mologni^{1

2}, Sébastien Tardy^{3

4

5}, Alfonso Zambon⁶, Alexandre Orsato^{3

7}, William H Bisson^{4

8}, Monica Ceccon¹, Michela Viltadi¹, Joseph D'Attoma³, Sara Pannilunghi^{4

5}, Vito Vece^{1

9}, Jerome Bertho², Peter Goekjian^{2

3}, Leonardo Scapozza^{2

4

5}, Carlo Gambacorti-Passerini^{1

2}

Affiliations

¹ Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy.
² Galkem srl, Monza 20900, Italy.
³ Laboratoire Chimie Organique 2-Glycochimie, CNRS-Université Claude Bernard Lyon 1, Lyon 69100, France.
⁴ School of Pharmaceutical Sciences, University of Geneva, Geneva 1211, Switzerland.
⁵ Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva 1211, Switzerland.
⁶ Department of Chemistry and Geological Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy.
⁷ Department of Chemistry, Universidade Estadual de Londrina, Paraná 86057-970, Brazil.
⁸ Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97227, United States.
⁹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Abstract

The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, and evaluated a large series of azacarbazole inhibitors. Several lead compounds endowed with submicromolar potency were identified. Compound 149 showed selective inhibition of native and mutant drug-refractory ALK kinase in vitro as well as in a Ba/F3 model and in human ALK+ lymphoma cells. The three-dimensional (3D) structure of a 149:ALK-KD cocrystal is reported, showing extensive interaction through the hinge region and the catalytic lysine 1150.