Abstract 7017: Discovery and development of a highly co-operative and potent pan-KRAS degrader

Abstract KRAS is one of the most frequently mutated oncogenes in various cancers. KRAS G12D mutation is prevalent in 39% of pancreatic ductal adenocarcinoma (PDAC), 27% of colorectal cancer, 11% of non-small cell lung adenocarcinoma as well as in a subset of other solid tumors. KRAS G12V mutation is found in 31% of PDAC, 20% of colorectal cancer and 19% of non-small cell lung adenocarcinoma. KRASG12C mutations are found in 41% of non-small cell lung adenocarcinoma and 3-5% of colorectal cancers. Despite recent advances in small molecule KRAS inhibitors, a majority of KRAS alterations are not yet addressed. Further, in cases where inhibitors are available, resistance rapidly emerges. Eliminating all mutant KRAS using a targeted protein degradation approach may lead to superior efficacy relative to inhibiting the protein. We have identified a series of degraders through structure-based drug design and our Directed Neo-substrate Degrader (DNsD) approach, with very high co-operativity, potent pan-KRAS degradation activity and a desirable pharmacokinetic profile. The high co-operativity of pan-KRAS degraders was confirmed though Surface Plasmon Resonance (SPR) analysis. These degraders demonstrated significant degradation of KRAS in multiple KRAS mutant cell lines and showed mechanistic activity via the modulation of pERK levels leading to significant anti-proliferative activity. The KRAS degraders were found to be selective against HRAS and NRAS which was also confirmed using global proteomic analysis. Further, the development candidate molecule demonstrated significant and dose dependent tumor growth inhibition in multiple KRAS mutant xenograft models which was accompanied by sustained KRAS degradation. Notably, the development candidate compound has demonstrated excellent PK and tolerability in rodent and non-rodent tox species. IND enabling studies are ongoing to support clinical development. Citation Format: Dinesh Chikkanna, Madhu Aeluri, Leena Khare, Ravindra MV, Debajyoti Basak, Uday Bhat, Suraj T. Gore, Narmatha V, Shailesh V. Jadhav, K Y. Vasantha, Sivapriya Marappan, Megha Goyal, R N. Raghavendra, Amit A. Dhudashiya, Kiran Aithal, T Jagadeesh Kumar, D S. Suhas, K B. Charamanna, P Dharani, R Naveenkumar, Rahul B. Chavan , Randeep Bokalial, D S. Samiulla, Subhendu Mukherjee, Thomas Antony, Kavitha Nellore, Rajesh Eswarappa, Girish Chandrappa Daginakatte, Sanjeev Giri, Susanta Samajdar, Murali Ramachandra. Discovery and development of a highly co-operative and potent pan-KRAS degrader [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 7017.