Scaffold hopping identifies 6,8-disubstituted purines as novel anaplastic lymphoma kinase inhibitors

Laura Schlütke; Markus Immer; Lutz Preu; Frank Totzke; Christoph Schächtele; Michael H G Kubbutat; Conrad Kunick

doi:10.1016/j.ejpb.2017.03.011

Scaffold hopping identifies 6,8-disubstituted purines as novel anaplastic lymphoma kinase inhibitors

Eur J Pharm Biopharm. 2018 May:126:89-94. doi: 10.1016/j.ejpb.2017.03.011. Epub 2017 Mar 15.

Authors

Laura Schlütke¹, Markus Immer², Lutz Preu¹, Frank Totzke³, Christoph Schächtele³, Michael H G Kubbutat³, Conrad Kunick⁴

Affiliations

¹ Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraβe 55, 38106 Braunschweig, Germany.
² Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraβe 55, 38106 Braunschweig, Germany; Technische Universität Braunschweig, Center of Pharmaceutical Engineering (PVZ), Franz-Liszt-Straβe 35A, D-38106 Braunschweig, Germany.
³ ProQinase GmbH, Breisacher Straβe 117, 79106 Freiburg, Germany.
⁴ Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraβe 55, 38106 Braunschweig, Germany; Technische Universität Braunschweig, Center of Pharmaceutical Engineering (PVZ), Franz-Liszt-Straβe 35A, D-38106 Braunschweig, Germany. Electronic address: c.kunick@tu-braunschweig.de.

PMID: 28315448
DOI: 10.1016/j.ejpb.2017.03.011

Abstract

Rearrangements of anaplastic lymphoma kinase (ALK) are associated with several cancer diseases. Due to resistance development against existing ALK-inhibitors, new, structurally unrelated inhibitors are required. By a scaffold hopping strategy, 6,8-disubstituted purines were designed as analogues of similar ALK-inhibiting thieno[3,2-d]pyrimidines. While the new title compounds indeed inhibited ALK and several ALK mutants in submicromolar concentrations, they retained poor water solubility.

Keywords: Anaplastic lymphoma kinase, ALK; EML4-ALK fusion; Gatekeeper mutation; Protein kinase inhibitor; Purine; Scaffold hopping; Solubility; Thieno[3,2-d]pyrimidine; c-Met.

MeSH terms

Anaplastic Lymphoma Kinase
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Binding Sites / drug effects
Binding Sites / physiology
Humans
Molecular Docking Simulation / methods
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein Structure, Tertiary
Purines / chemistry*
Purines / metabolism
Purines / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Purines
ALK protein, human
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases