In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.

Highlights d A comprehensive degrader molecule (PROTAC) library for KRAS G12C is described d Lead compound degrades GFP-KRAS G12C in a CRBNdependent manner d Challenges and solutions for achieving endogenous KRAS G12C degradation are discussed

Highlights d Development of a CDK6-selective small-molecule degrader d Mechanistically understood selectivity via differential ternary complex formation d Profiling of consequences of CDK6 degradation on signaling and gene regulation d Precise exploitation of genetic dependencies through homolog-selective degradation Authors

Effective and sustained inhibition of non-enzymatic oncogenic driver proteins represents a major pharmacologic challenge. The clinical success of thalidomide analogs demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets 1 – 3 , but a significant subset of proteins are recalcitrant to targeted protein degradation using current approaches 4 , 5 . Here we report an alternative mechanism, whereby a small molecule induces highly specific, reversible polymerization, sequestration into cellular foci, and subsequent degradation of a target protein. BI-3802 is a small molecule that binds the BTB domain of the oncogenic transcription factor BCL6 and results in proteasomal degradation 6 . We used cryo-EM to reveal how the solvent-exposed moiety of a BCL6 inhibitor contributes to a composite ligand/protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to superior pharmacological activity. These findings create new avenues for the development of therapeutics and synthetic biology.

The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it is not selective for BTK, and multiple mechanisms of resistance, including the C481S-BTK mutation, can compromise its efficacy. We hypothesized that small-molecule–induced BTK degradation may overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in potent suppression of signaling and proliferation in cancer cells and that BTK degraders efficiently degrade C481S-BTK. Moreover, we discovered DD-03-171, an optimized lead compound that exhibits enhanced antiproliferative effects on mantle cell lymphoma (MCL) cells in vitro by degrading BTK, IKFZ1, and IKFZ3 as well as efficacy against patient-derived xenografts in vivo. Thus, “triple degradation” may be an effective therapeutic approach for treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.

Highlights d Phenothiazine analog iHAP1 activates PP2A-B56ε and potently kills malignant cells d iHAP1 does not inhibit dopamine signaling or cause prohibitive neurologic toxicity d PP2A-B56ε dephosphorylates MYBL2-Ser241, causing prometaphase arrest with apoptosis d Other PP2A activators, SMAPs, activate PP2A-B55a and target different substrates

The zinc finger transcription factor Helios is critical for maintaining the identity, anergic phenotype, and suppressive activity of regulatory T cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor Cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of regulatory T cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity.

Highlights d A selective Wee1 degrader was generated by conjugating pomalidomide to AZD1775 d Wee1 degradation induced G2/M accumulation at lower doses than Wee1 inhibition d Wee1 degradation synergized with Olaparib in ovarian cancer cells