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Previously, we identified that AP-1 transcription factor FOSL1 is required to maintain cancer stem cells (CSCs) in HNSCC, and an AP-1 inhibitor, T-5224, can eliminate HNSCC CSCs. However, its potency is relatively low, and furthermore, whether T-5224 eradicates CSCs through targeting FOSL1 and whether FOSL1 serves as an effective target for eliminating CSCs in HNSCC, require further validation. We first found that T-5224 can bind to FOSL1 directly. As a proof-of-principle, several cereblon (CRBN)-recruiting PROTACs were designed and synthesized using T-5224 as a warhead for more effective of targeting FOSL1. The top compound can potently degrade FOSL1 in HNSCC, thereby effectively eliminating CSCs to suppress HNSCC tumorigenesis, with around 30 to 100-fold improved potency over T-5224. In summary, our study further validates FOSL1 as an effective target for eliminating CSCs in HNSCC and suggests that PROTACs may provide a unique molecular tool for the development of novel molecules for targeting FOSL1., 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 © 2024 Elsevier Inc. All rights reserved.)

The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management., 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 © 2024 Elsevier Inc. All rights reserved.)

Opioid Use Disorder (OUD) can be described as intense preoccupation with using or obtaining opioids despite the negative consequences associated with their use. As the number of OUD cases in the U.S. increase, so do the number of opioid-related overdose deaths. In 2022, opioid-related overdose became the No. 1 cause of death for individuals in the U.S. between the ages of 25 and 64 years of age. Because of the introduction of highly potent synthetic opioids (e.g. fentanyl) to the illicit drug market, there is an urgent need for therapeutics that successfully reduce the number of overdoses and can help OUD patients maintain sobriety. Most abused opioids stimulate the mu-opioid receptor (MOR) and activation of this receptor can lead to positive (e.g., euphoria) consequences. However, the negative side effects of MOR stimulation can be fatal (e.g., sedation, respiratory depression). Therefore, the MOR is an attractive target for developing medications to treat OUD. Current FDA drugs include MOR agonists that aid in detoxification and relapse prevention, and MOR antagonists that also serve as maintenance therapies or reverse overdose. These medications are limited by their abuse potential, adverse effects, or pharmacological profiles which leaves ample room for research into designing new chemical entities with optimal physiological effects. These includes, orthosteric ligands that target the primary binding site of the MOR, allosteric ligands that positively, negatively, or "silently" modulate receptor function, and lastly, bitopic ligands target both the orthosteric and allosteric sites simultaneously., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Wnt/β-catenin signaling pathway plays extensive roles in cancer initiation, proliferation, and development, and has been implicated in the regulation of stem cells in the intestinal crypt, widely accepted as responsible for colorectal cancer (CRC) origination. This pathway has been a target of interest for many years for chemotherapeutic development of CRC due to its implication in most cases. Previously, a series of naphthoquinone analogs have been identified to inhibit the Wnt/β-catenin. It was postulated that these compounds exhibit their inhibitory activity via binding to β-catenin at the β-catenin/TCF4 interaction interface. In this study, we aimed to further define the critical pharmacophore for these compounds and verify their mechanisms of action for their abilities to inhibit the Wnt/β-catenin signaling pathway. Interestingly, our data suggested two of the compounds, compounds 3 and 6, may potently inhibit the Wnt/β-catenin signaling pathway via inhibition of the TCF4/DNA interaction, a novel finding compared to previous studies on these compounds. Our computational studies suggested that the compounds bound within the DNA binding HMG-box domain of TCF4 to elicit their inhibitory action. These compounds inhibited Wnt signaling in a dose dependent manner, suppressed Wnt direct target genes and demonstrated unforeseen degradation of the TCF4 protein. Thus, this study revealed a potentially novel mechanism of action of the chloro-naphthoquinone as possibly a multi-targeting scaffold, which warrants further investigation in future drug discovery on the 'undruggable" TCF proteins and an aberrantly activated Wnt/β-catenin signaling pathway., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The functional interactions between opioid and chemokine receptors have been implicated in the pathological process of chronic pain. Mounting studies have indicated the possibility that a MOR-CXCR4 heterodimer may be involved in nociception and related pharmacologic effects. Herein we have synthesized a series of bivalent ligands containing both MOR agonist and CXCR4 antagonist pharmacophores with an aim to investigate the functional interactions between these two receptors. In vitro studies demonstrated reasonable recognition of designed ligands at both respective receptors. Further antinociceptive testing in mice revealed compound 1a to be the most promising member of this series. Additional molecular modeling studies corroborated the findings observed. Taken together, we identified the first bivalent ligand 1a showing promising antinociceptive effect by targeting putative MOR-CXCR4 heterodimers, which may serve as a novel chemical probe to further develop more potent bivalent ligands with potential application in analgesic therapies for chronic pain management., (Copyright © 2022 Elsevier Inc. All rights reserved.)