Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. The disease-initiating event in most CRC cases is the loss of the Adenomatous Polyposis Coli (APC-LOF) gene. Strategies for targeting APC-LOF could provide an opportunity to intercept tumorigenesis in high-risk CRC, such as in Familial Adenomatous Polyposis (FAP) disease, a disease with high unmet medical need.
A novel synthetic lethality between APC-LOF and protein arginine methyltransferase (PRMT5) was discovered through phenotypic screening in isogenic organoid pairs. This discovery offered the opportunity to exploit PRMT5 inhibition for CRC interception.
To circumvent the well-known on-target cytopenias associated with orally bioavailable PRMT5 inhibitors, we sought to discover an oral, GI-restricted (GR) small molecule PRMT5 inhibitor for the interception of APC-LOF CRC.
We report on the discovery of GR-PRMT5 inhibitors, that showed a profile that could achieve low systemic exposure through: (1) minimal passive permeability and (2) maximized systemic clearance by incorporation of a metabolic soft spot. Next, we describe our in vivo pharmacokinetics evaluation workflow to assess GI-restriction, as well as the characterization of in vivo pharmacology and hematological toxicity.
This work culminated in the discovery of two SAM-competitive gut-restricted PRMT5 inhibitors: cpd. 1 and cpd. 2. Low bioavailability, i.e. F ≤ 0.6 %, was achieved for cpd. 1 and 2 in preclinical species (mouse, rat, dog), through a combination of low absorption and high (AO-mediated) clearance. Both compounds demonstrated in vivo colon pharmacodynamics (PD) at doses devoid of hematological adverse effects in mice. Moreover, efficacy was demonstrated by a significant reduction in the colon polyp count in a dextran sodium sulfate (DSS-) induced Apc^Min/+ mouse model with established colonic polyps. These results highlight that local (colon) concentrations are able and sufficient to diminish the number of established polyps, validating the envisioned GI-restricted strategy.

Kathleen Clancy

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