Heteroaryl-linked 5-(1H-benzimidazol-1-yl)-2-thiophenecarboxamides: potent inhibitors of polo-like kinase 1 (PLK1) with improved drug-like properties.
Potent inhibitors of PLK1 with acceptable solubility, mouse iv clearance, and reduced CYP450 inhibition were identified. Drug-like properties were improved using a heteroaryl ring as a functional handle for manipulation of inhibitors' physiochemical and DMPK properties.
Rheault
Tara R
TR
GlaxoSmithKline, Research Triangle Park, NC 27709, USA. tara.r.rheault@gsk.com
Donaldson
Kelly H
KH
Badiang-Alberti
Jennifer G
JG
Davis-Ward
Ronda G
RG
Andrews
C Webb
CW
Bambal
Ramesh
R
Jackson
Jeffrey R
JR
Cheung
Mui
M
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D003198:Computer Simulation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry; D000097869:Polo-Like Kinase 1
D000577:Amides; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D000097869:Polo-Like Kinase 1