Cigall Kadoch, PhD
Professor of Pediatric Oncology and Meredith and Billy Starr Investigator, Dana-Farber Investigator, Howard Hughes Medical Institute
Cigall Kadoch, PhD, Associate Professor of Pediatric Oncology at Dana-Farber and Harvard Medical School, is spearheading a transformative project to understand and target intrinsically disordered regions (IDRs) of chromatin regulatory proteins that control the opening and closing of chromatin, the 3D structure of DNA wrapped around proteins in a cell’s nucleus. Her team’s innovative approach brings together multiple methodologies to probe the very factors that are frequently mutated and known to uphold cancer growth.
Newly supported by the Dana-Farber Accelerator, this project has the potential to redefine drug discovery for “undruggable” targets. Chromatin regulatory proteins have emerged as among the top-mutated and involved factors in cancer biology. “Such nuclear proteins are particularly enriched in disordered sequences that lack defined 3D structure, and because of that, we need to both understand their diverse functions and define new ways to alter their biochemical properties and interactions,” says Kadoch, explaining the goal of her current work.
Over 40% of a cell’s protein content (cellular proteome) consists of IDRs, which are challenging to target therapeutically due to their lack of defined structure. These regions are crucial in numerous biological processes, yet their roles remain poorly understood. Kadoch’s lab has identified that IDRs play a pivotal role in the function of key chromatin regulatory complexes known as mammalian SWI/SNF (mSWI/SNF or BAF) complexes, which are heavily implicated in cancer. “These complexes are the most frequently mutated entities in all of human cancer, second only to the well-known tumor suppressor, TP53, and represent top vulnerabilities across a range of disease states”, she explains.
If we can develop new proof-of-concept approaches on a few top cancer targets, our approaches could open the floodgates for efforts across a broader range of factors that have been historically recalcitrant to small molecule targeting
Cigall Kadoch
Identifying First-in-Class IDR Engagers
Kadoch’s recent work published in Cell 1 in 2023 demonstrated that specific amino acid sequences, or “sequence grammars,” are crucial for IDR function. “We learned that specific grammars, or strings of amino acids, are required to enable cell type- and cancer-specific interactions,” Kadoch emphasizes. By understanding these grammars, the team hopes to alter the function of various chromatin regulatory IDRs selectively.
”If we can develop new proof-of-concept approaches on a few top cancer targets, our approaches could open the floodgates for efforts across a broader range of factors that have been historically recalcitrant to small molecule targeting,” Kadoch states. By targeting these IDRs and their interfaces, the research could lead to more effective treatments for cancers that currently lack targeted therapies.
Applications Beyond Cancer
Beyond cancer, the insights gained from this research could have far-reaching implications for drug discovery across various human diseases. The ability to target IDRs could unlock new therapeutic possibilities for immune conditions, neurodevelopmental disorders and other diseases involving targets that currently lack conventional small molecules. The Dana-Farber Accelerator funding is key in establishing a platform to interrogate IDRs of chromatin regulatory proteins and subject them to chemical intervention. This support allows the team to explore new strategies for understanding and targeting disordered regions.
Team Members: Cigall Kadoch, PhD, Whitney Lieberman
Team Members
Whitney Lieberman
Graduate Student, Kadoch Lab
