Scaffold hopping identifies 6,8-disubstituted purines as novel anaplastic lymphoma kinase inhibitors.
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.
Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraβe 55, 38106 Braunschweig, Germany.
Laura
L
Schlütke
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.
Markus
M
Immer
Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraβe 55, 38106 Braunschweig, Germany.
Lutz
L
Preu
ProQinase GmbH, Breisacher Straβe 117, 79106 Freiburg, Germany.
Frank
F
Totzke
ProQinase GmbH, Breisacher Straβe 117, 79106 Freiburg, Germany.
Christoph
C
Schächtele
ProQinase GmbH, Breisacher Straβe 117, 79106 Freiburg, Germany.
Michael H G
MHG
Kubbutat
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.
Conrad
C
Kunick
D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
Anaplastic lymphoma kinase, ALK; EML4-ALK fusion; Gatekeeper mutation; Protein kinase inhibitor; Purine; Scaffold hopping; Solubility; Thieno[3,2-d]pyrimidine; c-Met