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3H-PYRAZOLO[4,3-F]QUINOLINE MOIETY AS A NOVEL PRIVILEGED KINASE INHIBITOR

thesis
posted on 26.04.2022, 18:15 by Delmis E HernandezDelmis E Hernandez

  

Using a version of the Povarov-Doebner reaction, we were able to identify and develop a novel kinase inhibitor scaffold that is tunable, selective, and able to target drug-resistant mutant kinases. The 3H-pyrazolo[4,3-f]quinoline moiety was shown to be a privileged kinase inhibitor scaffold with a strong inhibition several different kinases. Herein, various 3H-pyrazolo[4,3-f]quinoline-containing compounds were synthesized quickly via the Povarov-Doebner multicomponent reaction. Our scaffold has demonstrated to potently inhibit FLT3 and CDK2 with nanomolar IC50 values. These FLT3 inhibitors were also shown to inhibit leukemic cell growth in a mouse disseminated AML model, establishing these 3H-pyrazolo[4,3-f]quinoline-containing compounds as lead compounds to develop into anti-cancer agents. The 3H-pyrazolo[4,3-f]quinoline moiety has potently inhibited ROCK1/2 with single digit nanomolar IC50 values, newly synthesized analogs with replacement of the boronic acid moiety with an amide also displayed inhibition of ROCK1/2. The most active compound (HSH3107) potently inhibits ROCK1/2 and although it did not display any antiproliferative effects against MDA-MB-231 (triple negative breast cancer cell line) at 1 µM, it did slow cell migration for up to 48 hours compared to DMSO control and Fasudil. Acyclic amide analogs of this scaffold have also led to the discovery of CDK12 and CDK13 inhibitors which can serve as a potential therapeutic in cancers where there may be no treatment strategy available or where resistance has emerged.

History

Degree Type

Doctor of Philosophy

Department

Chemistry

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Herman Sintim

Additional Committee Member 2

Chittaranjan Das

Additional Committee Member 3

Mingji Dai

Additional Committee Member 4

Gaurav Chopra