“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 [...]

“PROTAC 6” (GlaxoSmithKline (GSK) IAP-based selective RIPK2 degrader with prolonged in vivo PD)

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 [...]

Kymera’s KT-413 is a CRBN-based dual-mechanism degrader that degrades both IRAK4 and the transcription factors IKZF1/3, acting as an IMiD, with promising clinical activity for the treatment of ABC-like subtype of DLBCL. This fascinating case study demonstrates how a dual-mechanism degrader of IKZF1/3 and IRAK4 can be designed to maximize NF-κB inhibition while simultaneously upregulating the Type I interferon response. This approach restores the apoptotic response and enables oncogene-mediated cell death, resulting in a robust antiproliferative and pro-apoptotic effect in MYD88 mutants.

Tumors can evade the immune system through the recruitment of regulatory T cells (Treg) which limit the activation and expansion of effector T cells (Teff). IKZF2 (Helios) is an Ikaros transcription factor family member that is expressed in a majority of Treg cells [...]