The dominant problem of fragment approaches remains progressing hits to potency; yet surprisingly, best practice and processes are elusive. With crystal-based screening now routine, including at Diamond’s XChem facility supporting 30-50 campaigns annually, the problem is now acute. We are developing approaches to allow users to routinely progress their high-quality hits to measurable potency, and are exploring Machine Learning approaches to advancing straight to potency.

Although the evolution from initial fragment to advanced hit or lead is possible without routine crystallographic support, high-resolution structures of the protein–fragment complex greatly facilitate the process. However, it can often be challenging to routinely obtain these crystal structures. In these instances, NMR spectroscopy is the method of choice to guide the medicinal chemistry campaign. I present our recent case studies of NMR structure-based drug design for fragments.

Modulation of enzymes that modify RNA (epitranscriptomics) is gaining interest in drug discovery. Gotham Therapeutics and ZoBio are developing inhibitors of METTL3/METTL14, a SAM-dependent methyltransferase that modifies adenosine in mRNA to generate m6A and thereby regulates protein expression. Here we will present an update on progress.

Covalent chemical probes and drugs can display unmatched potency, selectivity and duration of action; however, their discovery is challenging. We constructed a library of mildly electrophilic fragments and characterized it by a new high-throughput thiol-reactivity assay. I will present the screening results of this library against a wide array of protein targets. We found selective hits for most targets, and combination with high-throughput crystallography allowed rapid progression in several cases.

Covalent fragments is a new lead generation technology based on principles of covalent drug design and fragment-based drug discovery. Advantages of covalent, relative to reversible fragments, is that covalent fragments have enhanced potency and crystal structures can be readily obtained of the fragments covalently bound to their protein target. I discuss covalent fragments for discovering E3 ligase inhibitors and future applications of covalent fragment technology in target-based and phenotypic screens.

WuXi AppTec has built a comprehensive drug discovery capability and capacity platform to improve the success of research and shorten the time of development. This presentation will discuss how to use our platform to support Pharma and Biotech drug discovery in ubiquitin-induced protein degradation more quickly and cost-effectively.

I report on several recent studies from my lab aimed at deriving potent, selective, cell-permeable, and efficacious protein-protein interaction (PPIs) antagonists by designing agents that can react with lysine, tyrosine or histidine, given that these are more ubiquitously present at binding interfaces of PPIs compared to cysteine. Examples will include potent and selective Lys- and Tyr-covalent agents targeting various PPIs, including IAPs, EphAs, and Bcl-2.

Inhibitor discovery for protein-protein interactions has proven difficult due to the large protein surface areas and dynamic interfaces. To address this challenge, structural biology approaches for fragment-based ligand discovery have had a significant impact on advancing small molecule inhibitors into the clinic. Inspired by the protein-observed NMR approach using ¹H-¹⁵N-HSQC NMR, we have applied a complementary protein-observed ¹⁹F NMR (PrOF NMR) approach using ¹⁹F-labeled side-chains that are enriched at protein-protein-interaction interfaces. This talk will describe several case studies where PrOF NMR has been applied for fragment screening, ligand deconstruction, and screening of protein mixtures. Several new inhibitors of epigenetic complexes will  be highlighted. 

We used FBDD approaches to create diverse chemical series that inhibit the unexplored cancer target, Vps34. Initially, the parameters which are most important for in vivo efficacy (potency, selectivity, PK-profile, tumor permeability, etc.) were unknown. Hence, we intentionally selected diverse fragment hits optimized to represent differing profiles for the parameters above. We share representative chemical structures. The in vivo results will be shown in a later presentation at this event.

Structural data is heavily relied on to develop weakly binding fragments into tight-binding leads. Unfortunately, structural data is not always available and this can prove to be a roadblock for exciting, but difficult, targets. We present a target and structure agnostic workflow: REFiL (Rapid Elaboration of Fragment into Leads), which was applied without structural data to the oncology target 53BP1 to expedite the delivery of improved potency leads.