The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing.
New drugs for neglected tropical diseases such as human African trypanosomiasis (HAT) are needed, yet drug discovery efforts are not often focused on this area due to cost. Target repurposing, achieved by the matching of essential parasite enzymes to those human enzymes that have been successfully inhibited by small molecule drugs, provides an attractive means by which new drug optimization programs can be pragmatically initiated. In this report we describe our results in repurposing an established class of human Aurora kinase inhibitors, typified by danusertib (1), which we have observed to be an inhibitor of trypanosomal Aurora kinase 1 (TbAUK1) and effective in parasite killing in vitro. Informed by homology modeling and docking, a series of analogs of 1 were prepared that explored the scope of the chemotype and provided a nearly 25-fold improvement in cellular selectivity for parasite cells over human cells.
Northeastern University, Department of Chemistry and Chemical Biology, Hurtig 102, 360 Huntington Avenue, Boston, MA 02115, USA.
Stefan O
SO
Ochiana
Vidya
V
Pandarinath
Zhouxi
Z
Wang
Rishika
R
Kapoor
Mary Jo
MJ
Ondrechen
Larry
L
Ruben
Michael P
MP
Pollastri
D064127:Aurora Kinases; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects*; D014352:Trypanosomiasis / Q000188:drug therapy
D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D014344:Trypanocidal Agents; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C523797:danusertib