June 23, 2020 -- The pathway to discovering and developing cancer therapies is not always linear, but well-designed models incorporating smart chemical innovations can provide elegant solutions to treatments for some of the most difficult cancers. Some of these efforts were shared on June 22 during the American Association for Cancer Research (AACR) 2020 virtual annual meeting II.
Synthetic chemistry is an integral component of many drug discovery cascades, particularly for small-molecule drug discovery. In a session titled "Chemistry to the Clinic: Lead Optimization Case Studies in Cancer Drug Discovery," scientists from Mirati Therapeutics and Revolution Medicines explained how they selected candidate molecules for cancer therapies and optimized them in early development.
If at first you don't succeed, use synthetic chemistry
To start, many companies begin with molecules that target particular pathways that are important in cancer metabolism. For example, unchecked KRAS signaling can lead to uncontrolled cell growth and is implicated in non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic cancer. More generally, defects in the RAS-MAPK signaling pathway can cause uncontrolled growth associated with cancers. Molecules acting against these pathways are often selected based on knowledge from scientific literature or internal expertise.
Although scientists may know how these pathways need to be blocked in order to prevent disease, finding a path toward drugs that actually achieve this is exceedingly difficult.
It is known that a G12C mutation in the oncogene KRAS impairs intrinsic GTPase activity by holding KRAS in the "on" state and increasing signaling. Traditional approaches have looked at inhibiting guanosine triphosphate (GTP) pathways, but this is challenging as it may also result in inhibition of properly functioning wildtype KRAS activity. Therefore, an alternative approach needs to be used to block mutated KRAS signaling.
To begin lead optimization, a team of researchers from Mirati Therapeutics identified a molecule that can bind to the switch II RAF-binding site on the guanosine diphosphate (GDP)-bound ("on") KRAS via covalent bonding to cysteine. Several iterations of the compound were tested in vivo to identify a compound called MRTX-1257 that has increased potency. The compound was proved to be efficacious in xenograph models; however, when tested in various animal models, the compound was not viable.
Therefore, the researchers went back to the drawing board to design alternative steric and electronic iterations that would attenuate direct uptake. They identified a new compound called MRTX-849 that offered a favorable balance between potency and stability. This compound binds to inactive, GDP-bound mutated KRAS to disrupt cellular signaling of the KRAS pathway.
Making an 'undruggable' target 'druggable'
Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a nonreceptor phosphotyrosine phosphatase that promotes tumor progression in many types of cancer when activated by regulating the RAS signaling pathway. Revolution Medicines has been interested in exploiting the allosteric nature of this molecule for over five years. The company leveraged a novel approach of locking the molecule in an autoinhibition position with the use of an allosteric inhibitor.
The company began with two tool compounds that had druglike chemical equity with promising lead-like profiles and scope for optimization. These compounds had a methyl group that occupies a pocket of the SHP2 autoinhibitory domain with partially hydrophobic characteristics. Next, researchers used structure-based drug discovery to guide modifications that would significantly increase the potency of their selected tool compound. The newly modified compound, which they termed early SAR compound, has the addition of an alcohol group.
Following this modification, researchers began optimization efforts on the newly modified tool compound which led to the identification of rodent tool compound RMC-4550. This compound was highly soluble and permeable with a clean chemical profile. They confirmed the allosteric mode of action with biochemical and biophysical analysis. The compound was then tested in vitro using cancer cell lines to confirm that it was a potent inhibitor of the RAS-MAPK pathway.
The molecule was further optimized for physiochemical properties and became the researchers' clinical candidate. RMC-4630 is a potent and highly selective inhibitor of SHP2 with high oral bioavailability. The compound exhibited a dose-dependent response in NSCLC xenograft models and was successfully used in combination with other NSCLC drugs. RMC-4630 was shown to have clinical activity against tumors with certain RAS pathway mutations, particularly NSCLC harboring the KRAS G12C mutation.
RMC-4630 is undergoing broad clinical development as a monotherapy in partnership with Sanofi, and as a combination therapy in various collaborations with Roche and Amgen.
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