Nurix recently unveiled their second clinical BTK degrader, NX-5948, which is in Ph. Ia/Ib for patients with advanced B-cell malignancies (NCT05131022). A novel CRBN ligand was developed to remove IKZF1/3 degradation activity, distinguishing NX-5948 from their earlier disclosed dual BTK-IKZF1/3 degrader NX-2127, which is currently in Ph. I for relapsed/refractory B-cell malignancies (NCT04830137). The potent BTK degrader NX-5948 has displayed CNS penetration preclinically, allowing for primary CNS lymphoma (PCNSL) participants to be included in the clinical study.

“compound 23” is a selective CRBN-based degrader of the pseudokinase, IRAK3, with in vitro activity in primary human cells. A volcano plot shows remarkable separation between IRAK3 degradation vs. most other proteins, with very little activity against family members IRAK1 and IRAK4. The authors were able to quickly generate this degrader from [...]

The Michigan bifunctional degrader, ARD-2585 , is similar to the Arvinas molecule, ARV-110 that was recently disclosed at AACR 2021. ARV-110 is a first-in-class, potent, and orally active AR degrader in clinical development, but understandably hasn’t had much published on it yet given the competitive environment. The publication of ARD-2585 [...]

A second-generation AR bifunctional degrader for drug-resistant prostate cancer. ARV-766 is Arvinas’ second bifunctional CRL4 CRBN E3 ligase-based androgen receptor (AR) degrader to enter the clinic for the treatment of prostate cancer (PCa), after ARV-110 (bavdegalutamide) . The glutarimide recruiting element is notable as it is simpler than [...]

The Arvinas ER chimeric degrader, ARV-471 , is an oral, bioavailable ER degrading CRBN-based  PROTAC for the treatment of patients with ER+/HER2- breast cancer. Along with ARV-110 , it is one of the first chimeric degraders to enter a Ph. II clinical trial. It was first disclosed at AACR in early 2021, and though the molecules have not been [...]