"Discovery, preclinical and early clinical development of eCF506/NXP900: the first total SRC inhibitor"

Host : Professor Alessio Ciulli

Venue: CeTPD Seminar Room

Summary

Increased activity of the non-receptor tyrosine kinase SRC has been linked to cell proliferation, migration and drug resistance in most solid malignancies, including breast, colon and prostate cancer. We developed the first small molecule inhibitor, eCF506 (now NXP900), that displays sub-nanomolar potency against SRC family kinases and high selectivity over the rest of the kinome, including a thousand-fold selectivity over ABL kinase. After a brief historical overview of the protein SRC and its role in cancer, I will talk about the discovery and preclinical development of NXP900, which displays a ‘conformation selective’ mode of blocking the activity of this non-receptor tyrosine kinase, leading to both inhibition of enzymatic activity and scaffolding properties. Structural, molecular biology and phenotypic data reveal the striking differences and therapeutic advantages between the mechanism of action of NXP900 compared to existing clinical SRC/ABL inhibitors. I will also show that the inhibition mode of NXP900 translates into increased antitumor efficacy and tolerability in mouse models of breast cancer, bone metastasis and other malignancies, and will finish the talk with an update on the extended phase 1 clinical trial currently ongoing in USA.

Bio

Asier completed an MPharm at the Universidad de Granada (1999), where he later completed a PhD in Medicinal Chemistry (2004) under the supervision of Prof Antonio Espinosa. After postdoctoral work in the fields of cell delivery and chemical biology with Prof Mark Bradley at the School of Chemistry of the University of Edinburgh, he took a group leader position in 2010 at the Institute of Genetics and Cancer and created the first chemistry lab of the Institute. He was promoted to Reader in 2015 and Full Professor of Medicinal Chemistry in 2018. His lab is interested in the development of novel chemical strategies to improve the efficacy and safety of cancer treatment, including novel prodrug approaches and small molecule kinase inhibitors. His lab discovered the clinical candidate NXP900, which was licensed to Nuvectis Pharma and is currently in clinical trials. He recently received the CRH Innovation and Entrepreneurship Award 2024 - Further, Faster, Together - for his collaboration with industry to bring NXP900 to the clinic and is the RSC BMCS Lectureship Award 2024/2025.

For more information, see www.boomchemistry.com