Fragment-to-Lead Medicinal Chemistry Publications in 2022.

This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015-2022. In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911).

Fragment-to-Lead Medicinal Chemistry Publications in 2021.

This Perspective is the seventh in an annual series that summarizes successful Fragment-to-Lead (F2L) case studies published in a given year. A tabulated summary of relevant articles published in 2021 is provided, and features such as target class, screening methods, and ligand efficiency are discussed, both for the 2021 examples and for the combined examples over the years 2015-2021. In addition, trends and new developments in the field are summarized. In particular, the use of structural information in fragment-based drug discovery is discussed.

Introduction to the themed collection on fragment-based drug discovery.

Guest editors David Rees, Anna Hirsch and Daniel Erlanson introduce the RSC Medicinal Chemistry themed collection on fragment-based drug discovery.

Fragment-to-Lead Medicinal Chemistry Publications in 2020.

Fragment-based drug discovery (FBDD) continues to evolve and make an impact in the pharmaceutical sciences. We summarize successful fragment-to-lead studies that were published in 2020. Having systematically analyzed annual scientific outputs since 2015, we discuss trends and best practices in terms of fragment libraries, target proteins, screening technologies, hit-optimization strategies, and the properties of hit fragments and the leads resulting from them. As well as the tabulated Fragment-to-Lead (F2L) programs, our 2020 literature review identifies several trends and innovations that promise to further increase the success of FBDD. These include developing structurally novel screening fragments, improving fragment-screening technologies, using new computer-aided design and virtual screening approaches, and combining FBDD with other innovative drug-discovery technologies.

Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization.

Targeting mutant KRAS.

The protein KRAS has for decades been considered a holy grail of cancer drug discovery. For most of that time, it has also been considered undruggable. Since 2018, five compounds have entered the clinic targeting a single mutant form of KRAS, G12C. Here, we review each of these compounds along with additional approaches to targeting this and other mutants. Remaining challenges include expanding the identification of inhibitors to a broader range of known mutants and to conformations of the protein more likely to avoid development of resistance.

Fragment-to-Lead Medicinal Chemistry Publications in 2019.

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.

Fragment-to-Lead Medicinal Chemistry Publications in 2018.

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.

Discovery of N-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C.

KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRASG12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRASG12C with submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.

Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens.

Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures.

Fragment-based drug discovery typically requires an interplay between screening methods, structural methods, and medicinal chemistry. X-ray crystallography is generally the method of choice to obtain three-dimensional structures of the bound ligand/protein complex, but this can sometimes be difficult, particularly for early, low-affinity fragment hits. In this Perspective, we discuss strategies to advance and evolve fragments in the absence of crystal structures of protein-fragment complexes, although the structure of the unliganded protein may be available. The strategies can involve other structural techniques, such as NMR spectroscopy, molecular modeling, or a variety of chemical approaches. Often, these strategies are aimed at guiding evolution of initial fragment hits to a stage where crystal structures can be obtained for further structure-based optimization.

Fragment-to-Lead Medicinal Chemistry Publications in 2017.

This Miniperspective is the third in a series reviewing fragment-to-lead publications from a given year. Following our reviews for 2015 and 2016, this Miniperspective provides tabulated summaries of relevant articles published in 2017 along with some general observations. In addition, we discuss insights obtained from analysis of the combined data set of 85 examples from all three years of publications.

Fragment-to-Lead Medicinal Chemistry Publications in 2016.

The popularity of fragment-based drug discovery (FBDD) is demonstrated by the number of recent successful fragment-to-lead (F2L) publications. This Miniperspective provides a tabulated summary of the F2L literature published in the year 2016, along with discussion of general trends. It uses the same format as our summary of the 2015 literature and is intended to be a resource for both FBDD practitioners and medicinal chemists in general.

Fragment-to-Lead Medicinal Chemistry Publications in 2015.

Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will provide a useful point of reference for both FBDD practitioners and the wider medicinal chemistry community.

Twenty years on: the impact of fragments on drug discovery.

After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.

Foreword: Pacific Fragments.

Pacific, which is derived from the Latin pac, means peaceful. [...].

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia.

Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function; it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia.

Learning from PAINful lessons.

Chemical probes are important both as tools to understand biology and as starting points for drug leads, but not every active molecule makes a good probe; many react nonspecifically with thiols. These promiscuous inhibitors are worse than useless because they can mislead researchers and muddy the literature. Understanding the mechanisms of such compounds can prevent scientists from following false hits down blind alleys.

Validity of ligand efficiency metrics.

A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists.