Understanding and Improving the Membrane Permeability of VH032-Based PROTACs
Selective protein degradation using proteolysis targeting chimeras (PROTACs) is an emerging strategy in medicinal chemistry and chemical biology that faces significant translational challenges. Namely, this strategy requires heterobifunctional molecules that typically possess physicochemical properties (e.g., high molecular weight and hydrogen bond donor/acceptor counts) that disfavor cellular permeability, thus prohibiting target engagement. In this issue, Lokey and collaborators (DOI: 10.1021/acsmedchemlett.0c00265) evaluate the membrane permeability of a series of PROTACs with two goals: developing a model for predicting membrane permeability for this class of molecules and identifying structural features of PROTAC linkers that modulate membrane permeability. By evaluating linkers of distinct length and chemical composition, the authors suggest tracking PAMPA data and lipophilic permeability efficiency metrics. Additionally, the authors note that compounds with high AlogP values show poor permeability and that, within a series, intramolecular shielding and/or engagement of H-bond donors can increase membrane permeability. Though more data are necessary to refine the proposed model, such structure–permeability relationships should facilitate the translational value of PROTACs by helping design bifunctional compounds with better in vitro and in vivo distribution properties.
Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5)
The S-adenosyl methionine (SAM)-dependent protein arginine methyltransferase (PRMT) family of enzymes regulate a variety of cellular processes including gene expression, signal transduction, mRNA splicing, and DNA repair. Within this family, PRMT5 is upregulated in several cancer types, and inhibition of PRMT5 with small molecules reduces growth of certain tumors. These previously explored inhibitors target the SAM cofactor and/or substrate binding sites. In this issue, Palte, Schneider, and co-workers from Merck & Co. (DOI: 10.1021/acsmedchemlett.9b00525) identify a new lead series of inhibitors that interact at a previously unidentified allosteric binding site. Crystallographic information indicates that their lead inhibitor, the enantiomer of which is a BACE1 inhibitor, induces significant structural changes in the protein backbone that in turn cause a previously rigid loop to occupy both the SAM and substrate binding sites, thus blocking the catalytic activity of the enzyme. Subsequent medicinal chemistry efforts to probe the flexibility and hydrophobicity of the pocket, coupled with crystallographic information about the conformational changes in the enzyme, suggest new opportunities for modulating this highly sought-after target through modulation of a novel site.
Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia
Blockage of voltage-gated sodium channels is a validated exploited mechanism of action for several clinically used drugs, though this drug class is typically associated with undesirable adverse effects and the potential for drug–drug interactions that require specialized dosing schedules. In this issue, Witty and co-workers (DOI: 10.1021/acsmedchemlett.0c00263) report the discovery of vixotrigene (formerly known as raxatrigine), a Nav blocker for which phase III trials are planned for treating trigeminal neuralgia, a disease with 150,000 cases diagnosed annually in the United States, and for which nonselective poorly tolerated NaV blockers are used clinically. To develop an efficacious and selective NaV blocker with improved safety profile with minimal hERG liability, the Convergence team conducted lead optimization studies that prioritized binding to the inactive state of the sodium channel relative to the active state of the channel (tonic selectivity), while simultaneously optimizing for pharmacokinetic properties favorable for oral dosing and CNS penetration. Robust optimization involving conformational constraint and stereochemical control delivered optimized analogs with >10-fold tonic selectivity for blocking the inactive state of the channels, appropriate physicochemical and in vitro and in vivo stability, and distribution properties for pharmacokinetic evaluation. Ultimately, the lead candidate, vixotrigene, demonstrated efficacy in in vivo models of neuropathic and inflammatory pain, an appropriate centrally mediated adverse effect profile, appropriate pharmacokinetic properties using four in vivo models, and minimal interactions with clinically relevant cytochromes P450, P-gp, and OATPs to promote as a clinical candidate.
