Discovery of Allosteric Non-Covalent KRAS Inhibitors

Description:

Background:

RAS mutations account for >15% of all human tumors, and of these ~85% are due to mutations in a particular RAS gene: KRAS. Currently, there are no approved drugs that can directly act on mutated KRAS to stop its cancer causing activities.

Dr. Gorfe at UTHealth has used a structure based computational ligand design approach followed by biophysical and cell biological experiments to discover a number of non-covalent allosteric inhibitors that target some of the most common mutant forms of KRAS including, G12V, G12D, G13D, Q61H as well as G12C.

 

Technology:

One of these ligands, named Compound 11, is a first-in-class pyrazolopyrimidine-based KRAS inhibitor with exceptionally good inhibitory profile. This compound:

- binds to GTP-KRAS with high affinity

- disrupts effector Raf binding

- reduces signal transduction through KRAS, and

- inhibits proliferation of cancer cells harboring mutant KRAS.

In addition, while compound 11 binds to active GTP-bound KRAS with a Kd of 200-1000 nM, it does not bind to inactive GDP-KRAS or to GDP- or GTP-bound NRAS and HRAS, two close homologs of KRAS.

 

 

 

Intellectual Property Status:

- Patent Pending

- Available for licensing

Patent Information:

The preceding is intended to be a non-confidential and limited description of a novel technology created at the University of Texas Health Science Center at Houston (UTHealth). This promotional material is not comprehensive in scope and should not replace company’s diligence in a thorough evaluation of the technology. Please contact the Office of Technology Management for more information regarding this technology.
For Information, Contact:
Hannah Nelson
Senior Technology License Associate
University of Texas Health Science Center At Houston
hannah.m.nelson@uth.tmc.edu
Inventors:
Keywords:
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