Drug Discovery News

Science from the field, chosen by the Enamine Germany team: new chemistry, targets and clinical results in drug discovery, with the papers behind them.

• One substituent apart. How BCL6 settled the argument between blocking and removing — For twenty years BCL6 refused to behave like a drug target. Its co-repressor groove is wide, shallow and polar, and BCL6's own binding partner sits there at only 30 µM, so any inhibitor had to beat a weak natural ligand on an unpromising surface. Boehringer Ingelheim eventually got to 3 nM, and then the pharmacology failed to follow: one of their compounds barely slowed lymphoma cells. Its equipotent near-twin, differing only in the group most chemists would treat as a solubilising handle, degraded BCL6 outright and killed the same cells. Three more years and a cryo-EM structure went into finding out why. On 14 December, Arvinas reports the first clinical data on ARV-393 (zaloblideg), an oral PROTAC BCL6 degrader, in patients with non-Hodgkin lymphoma. This review follows the chemistry that made that trial possible, from 79-6 at 129 µM through a subpocket holding five ordered water molecules to the two cereblon-recruiting degraders now in the clinic. It also reads the announcement carefully: what the poster will contain, what it will not, and the three things worth looking for in its PK/PD.
• When the Reaction Mixture Becomes the Screening Library — In direct-to-biology (D2B) screening, chemists test crude reaction mixtures in biological assays before purifying individual compounds. A promising result tells them which mixture to investigate. The next step is to identify the molecule responsible for the activity.
• A 100,000-Fold Difference: How Linker Geometry Transforms Bivalent EGFR Inhibitors — Connecting two molecules that bind neighboring pockets of the same protein seems like a straightforward way to improve potency. Each fragment already has its own binding interactions, so combining them should produce a stronger inhibitor. In practice, the connection can interfere with both.
• SOX10 and HaloPROTACs: Beyond Gene Silencing — A bioRxiv preprint from Purvis, Slavoff and colleagues at Yale uses a HaloTag fusion and the commercial degrader HaloPROTAC3 to remove SOX10 from patient-derived melanoma cells and to map the genes that depend on it. It shows what a tag-degrader can establish before a degrader for the native protein exists, and where that evidence stops: the data describe an engineered, overexpressed SOX10–HaloTag fusion, not the druggability of native SOX10. The work is a preprint and has not been peer reviewed.
• KT-333: When Chemistry Delivers, but Strategy Decides — KT-333 achieved up to 95% STAT3 degradation in patients, yet its development stopped after Phase I. What makes this PROTAC particularly interesting is its linker, which helps create an entirely new interaction surface between STAT3 and VHL. The clinical results demonstrated substantial target degradation and encouraging antitumor activity, although important questions remained.