Design and biological evaluation of substituted 5,7-dihydro-6 H-indolo[2,3- c]quinolin-6-one as novel selective Haspin inhibitors

Sreenivas Avula; Xudan Peng; Xingfen Lang; Micky Tortorella; Béatrice Josselin; Stéphane Bach; Stephane Bourg; Pascal Bonnet; Frédéric Buron; Sandrine Ruchaud; Sylvain Routier; Cleopatra Neagoie

doi:10.1080/14756366.2022.2082419

Design and biological evaluation of substituted 5,7-dihydro-6 H-indolo[2,3- c]quinolin-6-one as novel selective Haspin inhibitors

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1632-1650. doi: 10.1080/14756366.2022.2082419.

Authors

Sreenivas Avula¹, Xudan Peng¹, Xingfen Lang¹, Micky Tortorella^{1

2}, Béatrice Josselin^{3

4}, Stéphane Bach^{3

4}, Stephane Bourg⁵, Pascal Bonnet⁵, Frédéric Buron⁵, Sandrine Ruchaud³, Sylvain Routier⁵, Cleopatra Neagoie^{1

2}

Affiliations

¹ Guangzhou Institute of Biomedicine and Health, Chinese Academy of Science, Guangzhou, China.
² Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Science, Hong Kong SAR, China.
³ Sorbonne Université/CNRS UMR8227, Roscoff cedex, France.
⁴ Sorbonne Université/CNRS FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Roscoff cedex, France.
⁵ Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Orleans, France.

Abstract

A library of substituted indolo[2,3-c]quinolone-6-ones was developed as simplified Lamellarin isosters. Synthesis was achieved from indole after a four-step pathway sequence involving iodination, a Suzuki-Miyaura cross-coupling reaction, and a reduction/lactamization sequence. The inhibitory activity of the 22 novel derivatives was assessed on Haspin kinase. Two of them possessed an IC₅₀ of 1 and 2 nM with selectivity towards a panel of 10 other kinases including the parent kinases DYRK1A and CLK1. The most selective compound exerted additionally a very interesting cell effect on the osteosarcoma U-2 OS cell line.

Keywords: Haspin kinase; Indoloquinoline; cell viability; docking.

MeSH terms

Bone Neoplasms*
Humans
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases
Quinolones* / pharmacology
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Quinolones
Protein Serine-Threonine Kinases

Grants and funding

This work was funded by “La Ligue contre le Cancer du Grand Ouest” committee (districts 29, 22, 56, 35, 45 and 79) in Région Centre Val de Loire, by the RTR Motivhealth. This research was supported by the Drug Discovery Pipeline of Guangzhou Institute of Biomedicine and Health, GIBH.