Drug discovery goes back to the bench: new pockets, new agonists, new chemistry

A new pocket on a tumor angiogenesis regulator

In a preprint posted to bioRxiv this week, researchers identified a unique N-terminal extension (Asn2-Lys19) on RhoJ, a Rho GTPase that regulates tumor angiogenesis, that is absent in Cdc42 and other Rho GTPases. That difference is the whole point: pockets shared across a protein family are hard to drug selectively, while a pocket that exists only on RhoJ offers a path to selective anti-angiogenic compounds. m:…2293

The team validated the pocket with the antifungal terconazole, which occupies the RhoJ N-terminal pocket and disrupts the RhoJ:PAK3 signaling interaction in a dose-dependent manner. They also built an eBRET2-based biosensor that provides a validated platform for monitoring the RhoJ:PAK3 interaction in live cells, which gives any follow-on screening campaign a ready-made readout. m:…2293

This suggests a broader lesson about where first-in-class chemistry comes from: not a better model of a known pocket, but a pocket nobody knew existed. RhoJ's N-terminal extension is the kind of target that only surfaces when structural biology is pointed at the parts of a protein family the textbooks treat as unremarkable. m:…2293

An agonist resurrected from an extinct gene

Another preprint took a more unusual starting material: a gene relic. Researchers grafted a 22-residue C-terminal fragment from an ostrich CXCL17 gene relic onto human or turtle CXCL17 and found that the fragment confers potent agonism to avian GPR25, with the C-terminus acting as the primary driver of species selectivity for GPR25 activation. m:…4673

The resulting turtle-ostrich and human-ostrich CXCL17 hybrids exhibit 5-13 nM potency at the mallard GPR25 receptor. The result is a proof of concept that functional protein fragments can be recovered from gene relics to engineer potent receptor agonists, which suggests that extinct or pseudogenized sequences are a largely untapped library of starting material for ligand engineering. m:…4673

The relic-mining angle generalizes. Genomes carry pseudogenized fragments that were once functional proteins, and this paper demonstrates they can be resurrected into potent ligands. This suggests extinct sequences could become a systematic source of novel protein fragments for receptor pharmacology, with the caveat that each fragment has to be shown to fold and behave as it did in its original context. m:…4673

A safer antiseizure scaffold that pairs with CBD

In epilepsy, the compound GAT1508 is presented as a selective activator of neuronal GIRK1/2 heterotetramers that exhibits superior antiseizure efficacy in PTZ-induced seizure models compared to the earlier tools ML297 and GiGA1. m:…1963

Two properties make it translationally interesting. First, GAT1508 does not significantly activate cardiac GIRK1/4 channels, suggesting reduced cardiovascular risk, which has been the major safety hurdle for GIRK-targeted epilepsy therapies. Second, it synergizes with cannabidiol to potentiate antiseizure effects in hippocampal slice recordings and in vivo models, opening a combination path for refractory epilepsy. m:…1963

The CBD synergy matters practically as well as scientifically: cannabidiol is already used in some epilepsy syndromes, so a compound that potentiates it has a clearer clinical path than a monotherapy with unknown drug interactions. The selectivity over cardiac channels is the piece that makes that path worth walking. m:…1963

New chemotypes against malaria and tumors

In a ChemRxiv preprint, 3H-1,5-benzodiazepine derivatives were evaluated against P. falciparum strains: compound 5o showed anti-plasmodial activity with IC50 values of 5.88 µM against PfD10 and 6.68 µM against PfW2, while compounds 5k and 5n demonstrated favorable selectivity profiles against HepG2 cells relative to the other derivatives. m:…7412

Computational analysis, including MM-GBSA and molecular dynamics simulations, identifies PfSET3 as a potential target for the scaffold, giving the chemistry a testable hypothesis to carry into the next round of optimization. m:…7412

Finally, genome mining of Fusarium sp. WA57 yielded fusariolones A-E and semifusariolone A, a distinct family of fungal polyketide-tropolone hybrids. The researchers defined the fusABCDEF gene set as the minimal biosynthetic pathway for the scaffold, and fusariolone A exhibits low-nanomolar antiproliferative activity with selectivity toward K562 and HT-29 cells, making it a credible lead for oncology development. m:…2357