Development of new drugs

Graphic showing KRAS inhibitor-2

A) Chemical structure of a KRAS inhibitor of the quinazoline chemotype designated “1.”
B) The crystal structure of mutant KRAS G12C in complex with compound 1 and GDP.
C) A dose titration with compound 1 shows inhibition of KRAS effector signaling through the MAPK pathway.

A continuing limitation in cancer treatment has been the lack of drugs that can target mutant proteins identified in human cancers. Fortunately, the range of targets that are considered “druggable” is continuously evolving.

Promising breakthrough

The Gray Lab has been successful at developing compounds to targets that were previously considered intractable. A major breakthrough came with the development of selective covalent CDK7 inhibitors. Since CDK7 is not a cell cycle kinase but implicated in transcriptional regulation, selective inhibition targets the transcriptional dependencies of several cancers, for example, neuroblastoma, small cell lung cancer, and triple negative breast cancers.

The first-in-class CDK7 inhibitor THZ1, developed in the Gray Lab, has shown promise in pre-clinical models. Additionally, Syros Pharmaceuticals has developed a clinical grade inhibitor, SY-1365, which is now entering phase I clinical trials. We are currently testing CDK7 inhibitors in genetically engineered mouse models and patient-derived xenografts for pancreatic cancer.

There are also ongoing efforts to directly target KRAS with an inhibitor. We have been successful in targeting KRAS mutant G12C with a tool compound, but this specific mutant is rare in pancreatic cancer.

Screening experimental compounds

In addition to specific candidate compounds such as those directed toward CDK7, the Hale Family Research Center is using libraries of experimental compounds from the Gray Lab for systematic screening in organoid models.

If a target is identified by genetic means in loss-of-function screens and validated, but no suitable inhibitor exists, the Gray Lab will attempt to generate a novel inhibitory compound through structure modeling.

We have also, in collaboration with Jay Bradner, developed a generalizable chemical degradation strategy. Selective “degraders,” which have been developed already for several target proteins, act as bifunctional small molecules, where one end of the molecule recruits E3 ubiquitin ligases such as cereblon via a phthalimide moiety, while the other end binds the target allosterically. We believe that this technology will allow us to ultimately target KRAS directly.

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