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We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. At this stage, we thought to evaluate the requirements for selectivity of inhibitors for POP over FAP and to evaluate molecular platforms that would enable the development of selective POP and dual POP/FAP inhibitors. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to one scaffold yielding new POP-selective inhibitors and a dual inhibitor equipotent to the only drug targeting FAP and POP that ever reached clinical trials., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CL pro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CL pro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CL pro . We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The MYC oncogene is considered to be a high priority target for clinical intervention in cancer patients due to its aberrant activation in more than 50% of human cancers. Direct small molecule inhibition of MYC has traditionally been hampered by its intrinsically disordered nature and lack of both binding site and enzymatic activity. In recent years, however, a number of strategies for indirectly targeting MYC have emerged, guided by the advent of protein structural information and the growing set of computational tools that can be used to accelerate the hit to lead process in medicinal chemistry. In this review, we provide an overview of small molecules developed for clinical applications of these strategies, which include stabilization of the MYC guanine quadruplex, inhibition of BET factor BRD4, and disruption of the MYC:MAX heterodimer. The recent identification of novel targets for indirect MYC inhibition at the protein level is also discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Research related to boronic acids, from synthetic development to materials to drug discovery, has skyrocketed in the past 20 years. In terms of drug discovery, the incorporation of boronic acids into medicinal chemistry endeavours has seen a steady increase in recent years. In fact, the Food and Drug Administration (FDA) and Health Canada have thus far approved five boronic acid drugs, three of which were approved in the past four years, and several others are in clinical trials. Boronic acids have several desirable properties that has led to their increased use, including potentially enhancing potency of drugs and/or improving their pharmacokinetics profile. This review explores discovery processes of boronic acid drugs. It begins with a brief scope of boron in natural products and in current drugs, followed by an investigation into the various rationalizations for boronic acid incorporation and the synthetic developments that focused on facilitating their addition into organic compounds. We hope that the knowledge we have assembled in this literature review will encourage medicinal chemists to consider the potential benefits of incorporating boronic acids into their future drug discovery endeavours., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the catalytic serine residue in this enzyme. While there have been many inhibitors discovered containing a nitrile to covalently bind to the catalytic serine, we have been investigating others, particularly boronic acids and boronic esters, the latter of which have been largely unexplored as covalent warheads. Herein we report a series of computationally-designed POP boronic ester pro-drug inhibitors exhibiting nanomolar-potencies in vitro as their active boronic acid species. These easily-accessible (1-2 step syntheses) compounds could facilitate future biochemical and biological studies of this enzyme's role in neurodegenerative diseases and cancer progression., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)