Neomorph is a molecular glue-focused biotech focused on pushing the boundaries of molecular glue degrader technology. We will describe how our platform discoveries have broadened the molecular glue target space and have translated to therapeutic opportunities with NEO-811, our clinical-stage ARNT degrader program, sharing key pieces of our preclinical data package. We will highlight the expanding promise of molecular glues as a transformative therapeutic modality to address otherwise-undruggable high value targets.

KRAS mutations drive tumorigenesis in cancers such as lung and pancreatic cancer. Autophagy supports tumor survival under metabolic stress, making it a promising therapeutic target in KRAS mutant tumors. ULK1 and ATG13 are core components of the complex that initiates autophagy. Using a HiBiT tagged ATG13 HTS assay, we identified SBP-1750, a ULK inhibitor that promotes ATG13 degradation, inhibits autophagy, suppresses tumor growth, and enhances anti tumor immunity in KRAS mutant cancer models.

Molecular glue mechanisms are notoriously challenging to discover systematically. Through large-scale cell line viability screens, we discovered molecular glues that reprogram the E3 ubiquitin ligase TRIM21 to degrade the nuclear pore complex (NPC). Proteomics and biochemical experiments demonstrated that the molecular glue brings TRIM21 into proximity with NUP98, resulting in NPC destruction and cancer cell apoptosis. Using structural insights, we developed optimized compounds with improved potency and chemical properties.

Precision degrader antibody conjugates (DACs) are an emerging modality that integrates the selectivity of antibody-directed delivery with targeted protein degradation. Here, we describe the discovery of dual SMARCA2/4 degrader payloads with potent degradation and antiproliferative activity together with linker technologies suitable for DAC applications. Conjugation of these payload–linker constructs to antibodies targeting diverse tumor antigens generated DACs with robust, antigen-dependent activity.

Despite the remarkable clinical success of trastuzumab deruxtecan (T-DXd) in HER2-positive and HER2-low cancers, acquired resistance remains a major challenge that limits long-term patient benefit. We have developed a new class of degrader-antibody conjugates (DACs) that combine tumor-selective antibody delivery with targeted protein degradation to eliminate key resistance drivers and enhance anti-tumor activity. This presentation will discuss the design principles, preclinical efficacy, and translational potential of DACs as a next-generation therapeutic modality for overcoming resistance and improving outcomes in refractory breast cancers.