Abstract 461: A screening platform to target intrinsically disordered regions (IDRs) of chromatin factors in disease

Abstract Aberrant chromatin is expanding as a new class of disease and resistance driver for multiple disease pathologies. While billions of dollars have been poured into drugging chromatin regulatory factors, the toxicity of previous approaches limits potential and promise. Conventional drug discovery strategies have focused on targeting only the stable interfaces of chromatin regulators. However, the specific regulation of chromatin function occurs in large part from the unstructured intrinsically disordered regions (IDRs). IDRs help specify the functionality of structured domains and play a critical role in regulating both physiological and disease-driving multi-protein assemblies. TippingPoint Biosciences has developed a first-of-a-kind screening platform that now enables targeting of IDRs in chromatin proteins by exploiting unique inter-molecular interfaces only found in disease driving chromatin states. TippingPoint’s approach should increase specificity, reduce toxicity and be less susceptible to drug resistance. To validate our drug discovery approach we are focusing our efforts on developing novel small molecule therapeutics for a rare pediatric brain tumor, Diffuse Intrinsic Pontine Glioma (DIPG), a disease driven by a very specific chromatin mutation that is difficult to target using conventional approaches. DIPG is driven by the H3.3 K27M mutation. Recognition of H3.3K27M by Polycomb Repressive Complex (PRC2), renders PRC2 inactive leading to a reduction in global H3K27me3. As a result, there are increased levels of H3K27ac and altered gene expression. Using our platform we generated a synthetic DIPG chromatin state, mimicking the stabilized interactions between PRC2-H3.3K27M chromatin IDRs. We successfully screened thousands of molecules against the DIPG chromatin state and identified molecules that disrupted PRC2 and H3K27M IDR interactions. These small molecule hits partially restored H3K27me3 levels, reduced H3K27ac levels, and decreased oligodendrocyte transcription factor 2 (OLIG2) expression in DIPG cell-lines to promote differentiation. These results successfully show that our platform can identify small molecules that uniquely target aberrant chromatin to rescue disease pathology. Citation Format: Laura Hsieh, Philamer Calses, Muryam Gourdet. A screening platform to target intrinsically disordered regions (IDRs) of chromatin factors in disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 461.