ABSTRACT Direct targeting of the oncoprotein MYC has long been attempted in cancer therapy, with limited success. We here identify a novel co-regulatory feedback loop of MYC and G1 to S phase transition protein 1 (GSPT1), where MYC promotes transcription of GSPT1, and GSPT1 senses stop codon of MYC to promote its translation. We report on the first-in-class dual MYC/GSPT1 protein degrader, GT19630. GT19630 significantly induced integrated stress response, abrogated oxidative phosphorylation through inhibition of the TCA cycle and induced cell death. Protein degradation of MYC was critical for efficacy of GT19630. GT19630 induced profound anti-proliferative effects and apoptosis agnostic to TP53 in a broad range of cancer cells, and is highly active in vivo in multiple, therapy-resistant hematologic and solid tumor models. Dual MYC/GSPT1 degradation was well tolerated in humanized Crbn I391V mice. In conclusion, we propose a novel treatment approach by directly targeting the MYC-GSPT1 axis in MYC-driven cancers. Statement of significance MYC has been considered an undruggable protein. We found a targetable, novel positive co-regulatory feedback of MYC and GSPT1, a key translation terminator. The dual MYC/GSPT1 degrader GT19630 is highly active in MYC-driven tumors, with moderate effects on humanized Crbn mice, providing opportunities to improve treatment outcome of MYC-driven cancers.

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.

h4>Background: /h4> Bruton’s tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Methods Fluorescence resonance energy transfer signals were used to assess BTK and cereblon (CRBN) ternary complex formation with Mab anti-6His-Eu cryptate and Mab anti-glutathione-S-transferase-XL665. BTK and CRBN binding activities were investigated using in vitro target binding assays. Subsequently, SDS-PAGE and western blotting of whole cell lysates was performed, followed by immunofluorescence analysis of TMD-8 cells. ELISA was performed in TMD-8 cells treated with 0.01 µM PROTAC, ibrutinib, acalabrutinib, ARQ-531, Binder, or MT-802 to measure CCL3 and CCL4 levels. Tandem ubiquitin-binding elements pull-down assay was used to characterize UBX-382 in Ramos cells. Various cells treated with inhibitor or PROTAC were assessed for proliferation and viability. Wild-type- or BTK-transfected cells were transplanted in CB17/SCID mice and the established tumors were assessed using immunohistochemistry. Results Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of DC 50 in DLBCL cell line. UBX-382 was effective on seven out of eight known BTK mutants in in vitro experiment and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for less than 2-weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. UBX-382 also provoked the cell-type-dependent and selective degradation of CRBN neo-substrates in various hematological cancer cells. Conclusions These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.