Fragment-to-Lead Medicinal Chemistry Publications in 2019

Abstract

Fragment-based drug discovery (FBDD) has grown and matured to a point where it is valuable to keep track of its extent and details of application. This Perspective summarizes successful fragment-to-lead stories published in 2019. It is the fifth in a series that started with literature published in 2015. The analysis of screening methods, optimization strategies, and molecular properties of hits and leads are presented in the hope of informing best practices for FBDD. Moreover, FBDD is constantly evolving, and the latest technologies and emerging trends are summarized. These include covalent FBDD, FBDD for the stabilization of proteins or protein–protein interactions, FBDD for enzyme activators, new screening technologies, and advances in library design and chemical synthesis.

Benzylic C–H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

“…Synthetic methods that join two fragments derived from abundant molecular building blocks, such as amide coupling and Pd-catalyzed cross-coupling, are the most widely used in drug-discovery. [1][2][3][4][5] Implementation of these methods using high-throughput experimentation (HTE) enables rapid creation of diverse complex molecules for biological screening. 6,7 Reactions capable of using C(sp 3 )-H bonds as sites for crosscoupling would be very appealing in this context.…”

Small-Molecule Inhibitors of Carboxylesterase Notum

“…Fragment-based drug design has proven to be an effective strategy for hit-finding across multiple protein target classes [46]. The screening of fragment libraries against Notum's druggable hydrophobic pocket is an attractive strategy and has led to the discovery of a number of hits with orthogonal chemical structures (Figure 4 & Table 1).…”

Emergent synthetic methods for the modular advancement of sp3-rich fragments

“…In this Perspective we outlined the need for methods to elaborate sp 3 -rich fragments, and have identied existing methodologies that are likely to be useful towards achieving this challenging goal. As an illustrative "thought experiment", we have considered how the methods discussed might be applied to develop known sp 3 -rich fragment hits, 4,[75][76][77][78] without an unreasonable level of prior manipulation to the hit's structure (Fig. 3).…”

“…[1][2][3] More than forty compounds derived from FBDD approaches have entered clinical trials, and four drugs have been approved. 4 In contrast to traditional high-throughput screening, which relies upon the availability of vast numbers ($10 6 to 10 9 ) of lead or drug sized compounds, FBDD enables the efficient 5,6 exploration of chemical space [7][8][9][10][11] by screening smaller collections ($10 3 ) of smaller compounds (typically <20 heavy atoms).…”