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Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the [CRL4.sup.CRBN] ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant acute myeloid leukemia., Introduction The recent discovery of thalidomide analogs that degrade G1 to S phase transition 1 (GSPT1) via the [CRL4.sup.CRBN] ubiquitin ligase highlighted GSPT1 as a novel potential therapeutic target in [...]

Phosphatidylinositol 5‐phosphate 4‐kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy‐dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non‐lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX‐4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated the PIP4K2C binder into TMX‐4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and degradable target, and that TMX‐4102 and TMX‐4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C. [ABSTRACT FROM AUTHOR]