TRI-611, a selective, brain-penetrant molecular glue degrader of ALK
Triana Biomedicines
https://doi.org/10.1038/s41586-026-10998-3
Drugs that inhibit the tyrosine kinase ALK currently target the ATP-binding site, which is conserved across tyrosine kinases. This impacts the selectivity of these drugs, which can limit their therapeutic index. In this work, Triana Biomedicines developed a small-molecule molecular glue degrader of ALK, which is currently in clinical trials for NSCLC. The compound acts by facilitating interactions between the E3 ligase CRBN and ALK. The targeted region of ALK sits away from the active site and is less conserved, resulting in a highly selective degrader.
Identification and SAR optimization of FBXO22-mediated TEAD Targeted Glue™ degraders
Amphista Therapeutics Ltd
https://doi.org/10.64898/2026.04.21.719895
Amphista have been using their Targeted GlueTM platform to develop drug-like degraders based on novel E3 ligases, with their first compound recently entering clinical trials. This preprint details the identification and optimisation of a TEAD degrader starting from a known inhibitor. They show that degradation is mediated through a reactive aldehyde, generated by the oxidation of an amine in the cell culture media, a known mechanism for degradation by FBXO22.
Toward Rational Design of Orally Bioavailable PROTACs: Development of a Fully Computational Oral Absorption Score
Arvinas Operations
https://doi.org/10.1021/acsmedchemlett.6c00305
Arvinas were the first biotech dedicated to PROTAC drug development and are behind vepdegestrant, which in May 2026 became the first PROTAC approved by the FDA. PROTACs often suffer from low bioavailability as their physicochemical properties sit outside the rule-of-5 space. Even for molecules that do show acceptable bioavailability, it is difficult to rationalise this with standard molecular descriptors. Here, Arvinas report comPASS, a fully computational scoring system for PROTAC absorption. The model relies on Rg and 3D PSA, which can be calculated from molecular dynamics simulations. Their analysis shows that PROTACs with extended linkers, which form a "rod-like" shape, are more likely to be orally absorbed.
FDA Approvals
A next-generation selective estrogen receptor degrader (SERD), granted accelerated approval with a CDK4/6 inhibitor for ESR1-mutant HR+/HER2– advanced breast cancer. The first approval to switch therapy based on ctDNA-detected resistance before radiographic progression.
Development Paper: https://doi.org/10.1021/acs.jmedchem.0c01163
An oral, irreversible, FGFR2-selective kinase inhibitor approved for previously treated FGFR2 fusion- or rearrangement-positive cholangiocarcinoma. Designed to avoid the broader FGFR-family activity of multi-FGFR inhibitors such as pemigatinib and futibatinib.
Development Paper: https://doi.org/10.1073/pnas.2317756121
A D1/D5 dopamine receptor partial agonist approved for Parkinson’s disease, either alone or with levodopa. The first approved agonist to selectively target D1/D5 rather than the D2/D3 receptors hit by existing dopamine agonists.
An ALK2 kinase inhibitor, active against the pathogenic R206H variant. Approved for fibrodysplasia ossificans progressiva after reducing new heterotopic bone formation versus placebo in the pivotal PROGRESS trial.
Development Paper: https://doi.org/10.1021/acsmedchemlett.5c00516
A thyroid hormone receptor agonist that enters cells independently of the defective MCT8 transporter. The first FDA-approved treatment for peripheral thyrotoxicosis in MCT8 deficiency (Allan-Herndon-Dudley syndrome).
Fast Track
A microtubule destabiliser that releases the immune signalling protein GEF-H1 to drive dendritic cell maturation. Granted Fast Track with docetaxel for non-squamous NSCLC that has progressed on anti-PD-(L)1 therapy and platinum chemotherapy.