In this Webinar, you will learn:
• A novel fragment-based drug discovery
• The development of p53 activators
• The high-throughput exploration of crude reaction mixtures through automated chemistry and X-ray crystallography
About this Webinar:
The p53 protein, often referred to as the "guardian of the genome," plays a critical role in regulating cell cycle, DNA repair, and apoptosis. Mutations or dysregulations in p53 are implicated in over half of all human cancers, making it a prime target for therapeutic intervention. Despite significant progress, developing effective p53 activators poses numerous challenges. As a nuclear transcription factor, p53 does not possess typical drug target features.
Fragment-Based Drug Discovery (FBDD) is a powerful approach in drug discovery that involves the identification of small chemical fragments binding to a target protein, which are then optimized into potent compounds. We recently developed a streamlined workflow integrating low-cost robotics and analytical techniques to rapidly gather structural data on binding sites (Grosjean et al). By using crystallographic fragment screens of the pleckstrin homology domain interacting protein (PHIP(2)), 1800 compounds were synthesized using an OpenTrons OT-1 liquid handler. The workflow included multi-step reactions, deconvolution of crude reaction mixtures with MScheck, and subsequent X-ray diffraction analysis. This efficient process identified 22 crystallographic hits, with one molecule showing notable binding affinity. This approach promises to significantly expedite the fragment-to-lead drug development process.
About John Spencer, PhD:
Dr. Spencer is a professor with industrial leadership in medicinal chemistry with a consistent track record of successful project delivery and IP generation. A driven leader with good communication skills and several million pounds of secured external research funding with >9000 citations, an H-index of 44, over 190 papers and 13 patents. He has 10 years’ experience as a medicinal chemist “at the bench” e.g. heading a parallel synthesis group for (Nobel Laureate) Sir James Black with clinical and preclinical candidates in cancer (CCK2 and PTH-1 antagonists) and proven research outputs in synthetic organic chemistry, drug discovery and palladium catalysis.
Dr. Spencer has a successful track record of mentoring junior colleagues in research strategy and grant bids and displayed strong citizenship; Director of Medicinal Chemistry/Drug Discovery Centre, previous Director of Research and Knowledge Exchange, committee member for new course generation (Pharmacy), PhD convenor for Department, UK grant committee chairman (RSC). International external profile; 2 editorial board positions, regular invited editor for journals, invited academic positions abroad, plenary and invited lectures. SAB member for Worldwide Cancer Research, Prostate Cancer UK, EPSRC Peer Review College member.
Recent Publications
[1] Boby ML, et al. Science. 2023 Nov 10;382(6671):eabo7201. [Content Brief]
[2] McGown A, et al. RSC Chem Biol. 2023 Aug 8;4(10):716-721. [Content Brief]
[3] Roe SM, et al. Biomolecules. 2023 Jun 28;13(7):1051. [Content Brief]
[4] Hassell Storm,et al. Helv. Chim. Acta. 2021 Jan 27; e2000214.
[5] Edmonds AK, et al. Org Biomol Chem. 2022 May 18;20(19):4021-4029. [Content Brief]
[6] Ditsiou A, et al. Sci Adv. 2020 Nov 13;6(46):eabc3099. [Content Brief]
[7] Cox O B, et al. Chem Sci. 2016 Mar 1;7(3):2322-2330. [Content Brief]
