VVD-065 / Bayer - LARVOL DELTA

A covalent allosteric molecular glue suppresses NRF2-dependent cancer growth. (PubMed, Cancer Discov) - P1 | "Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_Cys151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312)."

Journal • Oncology • Targeted Protein Degradation • KEAP1

A New Class of Molecular Glues: Double Allostery Restores KEAP1 Control of NRF2. (PubMed, Cancer Discov) - "Roy and colleagues describe VVD-065, a covalent allosteric molecular glue that binds KEAP1 at Cys151 to enhance KEAP1-CUL3 assembly, restore NRF2 ubiquitination and degradation, and selectively suppress NRF2-driven tumors by reactivating endogenous E3 ligase function. See related article by Roy et al., p. 953."

Journal • Oncology • Targeted Protein Degradation • KEAP1

Therapeutic targeting of NRF2 increases sensitivity to chemotherapy in various solid tumors (EORTC-NCI-AACR 2024) - "Consistent with NRF2's known role in chemoresistance, combining VVD-065 with chemotherapy agents such as cisplatin, nab-paclitaxel, 5-FU, and gemcitabine led to marked improvements compared to monotherapy groups...Our preclinical PDX trial revealed that squamous cancer types are particularly susceptible to NRF2 depletion. Additionally, combining VVD-065 with SOC chemotherapy resulted in more profound and durable responses."

Bladder Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • BRAF • KRAS