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Abstract Therapeutic options for aggressive and high-risk lymphomas, such as double-hit lymphoma (DHL), remain limited. As a novel therapeutic modality, molecular glue degraders represent a promising strategy by harnessing E3 ubiquitin ligases to selectively target oncogenic driver proteins for degradation. Here, we report INNO-235, a novel cereblon (CRBN)-binding molecular glue that concurrently degrades CK1α and GSPT1, effectively inducing apoptosis in DHL cells. Our previous studies demonstrated that selective CK1α molecular glue degraders possess therapeutic potential in certain types of B-cell lymphomas. Building upon this finding and aiming to explore the potential advantages of a multi-target degradation strategy, we rationally designed a unique CRBN-binding molecular glue library. Through library screening efforts, we identified INNO-235 with dual-targeting degrader of GSPT1 and CK1α. INNO-235 demonstrated potentanti-proliferative activity against diffuse large B-cell lymphoma (DLBCL) cell lines, with minimal cytotoxicity in peripheral blood mononuclear cells (PBMCs) from healthy donors. Notably, INNO-235 exhibited single-digit nanomolar antiproliferative activity in all tested DHL cell lines showing a tenfold increase in potency compared to MRT-2359, a GSPT1-selective degrader. Importantly INNO-235 retained robust efficacy in p53-mutant DHL DLBCL cell lines, which are resistant to INNO-220, a selective CK1α degrader. Mechanistic studies confirmed that INNO-235 degrades both GSPT1 and CK1α in a CRBN-dependent manner and maintains strong degradation activity across genetically diverse DHL DLBCL cell lines. Furthermore, we observed that INNO-235 treatment induced apoptosis in DHL DLBCL cell lines irrespective of p53 mutation status and concurrently caused G0/G1 phase arrest in p53 wild-type DHL cell lines. I n vivo evaluation using a Will-2 xenograft model revealed that oral administration of INNO-235 exhibited significant tumor growth inhibition compared to vehicle controls and overperformed either CK1α or GSPT1 single-targeting degrader. Remarkably, in the high-dose INNO-235 group (10mg/kg), half of the treated mice achieved complete tumor regression with no recurrence occurred during the study period. Ex vivo analysis of tumor tissues confirmed CK1α and GSPT1 degradation by INNO-235. To elucidate the mechanism of action of INNO-235, we employed RNA sequencing in Will-2 and found INNO-235 activates both p53 signaling and integrated stress response pathways. INNO-235 exerts its anti-proliferative effects on DHL cells through a dual mechanism. In wild type DHL DLBCL cell lines, INNO-235 triggers CK1α degradation-dependent stabilization and activation of p53 with concomitant p21 upregulation and driving apoptosis; concurrently, GSPT1 degradation induces phosphorylation of eIF2α and upregulates ATF4/CHOP, triggering the terminal integrated stress response. Additionally, we observed concomitant over 60% downregulation of oncogenic c-Myc protein, a key driver of DHL pathogenesis. Notably, CK1α selective degraders failed to inhibit p53-mutant DHL proliferation, whereas INNO-235 maintained nanomolar potency, highlighting the importance of dual-targeting for broad therapeutic efficacy. Collectively, INNO-235 represents a first-in-class, orally bioavailable CRBN-based molecular glue capable of concurrently degrading both GSPT1 and CK1α at nanomolar concentrations. By inducing classical apoptosis in p53 wild-type cells and p53-independent tumor cell apoptosis via the ISR pathway in p53-mutant cells, INNO-235 overcomes the limitations of single-target therapies. This dual targeting GSPT1 and CK1α for degradation presents an attractive therapeutic strategy with a single-agent for DHL across diverse genetic backgrounds. This work provides compelling rationale for clinical translation in genetically diverse high-grade lymphomas.