Abstract PR09: KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models

Abstract

KRAS is genomically altered in about one third of all human tumors. Due to its central role in oncogenesis, many attempts have been made in the last four decades to drug mutant KRAS, either directly or indirectly. Despite recent advances in targeting KRAS using small molecule inhibitors, the majority of KRAS alterations do not yet have an existing targeted therapy, and where inhibitors are available, resistance rapidly emerges. Thus, novel approaches to drugging KRAS are needed. Eliminating mutant KRAS using a targeted protein degradation approach may lead to superior efficacy relative to inhibiting the protein. KRAS PROTAC® degraders that selectively target the G12D mutant form of KRAS were identified and profiled in KRAS-dependent cancer models. In vitro, PROTAC degraders targeting the G12D mutant degrade KRAS with picomolar potency, robustly suppress MAPK and PI3K/AKT signaling, induce apoptosis, and have antiproliferative activity that is superior to known inhibitors. These molecules are selective for mutant KRAS G12D, neither degrading wild-type KRAS nor the related isoforms HRAS and NRAS. In vivo, these degraders can eliminate >95% of mutant KRAS from relevant xenograft models, induce apoptosis, and lead to tumor regression. Consistent with the extended pharmacodynamics often observed with PROTAC degraders, a single dose of a G12D PROTAC results in prolonged KRAS degradation and significant pERK suppression up to one week after administration. Combined, these data show that degrading mutant KRAS G12D in tumors is highly efficacious and may have advantages over inhibition, making it an exciting potential new approach for the treatment of KRAS mutant cancers. Citation Format: Kathryn Smith, Andrea Lopez-Arroyo, Jason Berk, Peter Hegan, Peter Nower, Samantha Tice, Aurelie Moutran, Jennifer Pizzano, Amanda Dowtin, Mark Bookbinder, Elizabeth Bortolon, Greg Cadelina, Fazlul Karim, Katie Digianantonio, Miklos Bekes, Jesus Medina. KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR09.

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D

“…More recently, Arvinas and Huadong Medicine reported their early effort of discovering potent KRAS G12D degraders at the AACR meeting and 2023 World Conference on Lung Cancer (WCLC 2023), respectively. 35,36 In addition, some other companies, such as Shanghai Pharma and Erasca, have also published patent applications describing KRAS G12D degraders. 37−39 In this study, we report our effort on the design, synthesis, and biological evaluation of a series of KRAS G12D PROTACs by conjugating the analogues of MRTX1133 and the VHL ligand through different types of linker moieties.…”

“…Astellas initiated a phase 1 clinical trial of their selective KRAS G12D PROTAC ASP3082 (structure was not disclosed, NCT05382559) in 2022. More recently, Arvinas and Huadong Medicine reported their early effort of discovering potent KRAS G12D degraders at the AACR meeting and 2023 World Conference on Lung Cancer (WCLC 2023), respectively. , In addition, some other companies, such as Shanghai Pharma and Erasca, have also published patent applications describing KRAS G12D degraders. − …”