Showing papers by "Peter Wipf published in 2020"
TL;DR: Recent advances in the discovery of small molecule inhibitors of p97, their optimization and characterization, and therapeutic potential are reviewed to highlight the potential for targeting p97 as a therapeutic approach in neurodegeneration, cancer and certain infectious diseases.
Abstract: The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a number of neurodegenerative diseases, and overexpression of wild type p97 is observed in numerous cancers. Furthermore, p97 activity has been shown to be essential for the replication of certain viruses, including poliovirus, herpes simplex virus (HSV), cytomegalovirus (CMV), and influenza. Taken together, these observations highlight the potential for targeting p97 as a therapeutic approach in neurodegeneration, cancer, and certain infectious diseases. This Perspective reviews recent advances in the discovery of small molecule inhibitors of p97, their optimization and characterization, and therapeutic potential.
60 citations
TL;DR: Findings indicate that mitigator targeting to three distinct cell death pathways increases survival after TBI, and there was optimal normalization to preirradiation levels of inflammatory cytokine and stress response protein levels in plasma, intestine and marrow.
Abstract: Mitigation of total-body irradiation (TBI) in C57BL/6 mice by two drugs, which target apoptosis and necroptosis respectively, increases survival compared to one drug alone. Here we investigated whether the biomarker (signature)directed addition of a third anti-ferroptosis drug further mitigated TBI effects. C57BL/6NTac female mice (30-33 g) received 9.25 Gy TBI, and 24 h or later received JP4-039 (20 mg/kg), necrostatin-1 (1.65 mg/kg) and/or lipoxygenase-15 inhibitor (baicalein) (50 mg/kg) in single-, dual- or three-drug regimens. Some animals were sacrificed at days 0, 1, 2, 3, 4 or 7 postirradiation, while the majority in each group were maintained beyond 30 days. For those mice sacrificed at the early time points, femur bone marrow, intestine (ileum), lung and blood plasma were collected and analyzed for radiation-induced and mitigator-modified levels of 33 pro-inflammatory and stress response proteins. Each single mitigator administered [JP4-039 (24 h), necrostatin-1 (48 h) or baicalein (24 h)] improved survival at day 30 after TBI to 25% (P = 0.0432, 0.2816 or 0.1120, respectively) compared to 5% survival of 9.25 Gy TBI controls. Mice were administered the drug individually based on weight (mg/kg). Drug vehicles comprised 30% cyclodextrin for JP4-039 and baicalein, and 10% Cremphor-EL/10% ethanol/80% water for necrostatin-1; thus, dual-vehicle controls were also tested. The dual-drug combinations further enhanced survival: necrostatin-1 (delayed to 72 h) with baicalein 40% (P = 0.0359); JP4-039 with necrostatin-1 50% (P = 0.0062); and JP4-039 with baicalein 60% (P = 0.0064). The three-drug regimen, timed to signature directed evidence of onset after TBI of each death pathway in marrow and intestine, further increased the 30-day survival to 75% (P = 0.0002), and there was optimal normalization to preirradiation levels of inflammatory cytokine and stress response protein levels in plasma, intestine and marrow. In contrast, lung protein levels were minimally altered by 9.25 Gy TBI or mitigators over 7 days. Significantly, elevated intestinal proteins at day 7 after TBI were reduced by necrostatin-1-containing regimens; however, normalization of plasma protein levels at day 7 required the addition of JP4-039 and baicalein. These findings indicate that mitigator targeting to three distinct cell death pathways increases survival after TBI.
33 citations
TL;DR: This Viewpoint highlights the complexity of the protein homeostasis network and discusses different approaches for modulating Hsp70 activity, including the use of a chemical reaction development-inspired library of Hsp 70 agonists and antagonists.
Abstract: The unfolded protein response (UPR) is a cellular stress response mechanism that is critical for cell survival. Pharmacological modulation of the ATPase activity of the chaperone Hsp70 can trigger ...
17 citations
TL;DR: A new variant of the intramolecular Diels-Alder oxazole (IMDAO) cycloaddition that provides direct access to 6-azaindoles was developed.
16 citations
TL;DR: Second-generation probiotics appear to be valuable for mitigation of TBI, and radiation protection during therapeutic total abdominal irradiation.
Abstract: Background/aim Intestinal damage induced by total body irradiation (TBI) reduces leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)-expressing stem cells, goblet, and Paneth cells, breaching the epithelial lining, and facilitating bacterial translocation, sepsis, and death. Materials and methods Survival was measured after TBI in animals that received wild-type or recombinant bacteria producing interleukin-22 (IL-22). Changes in survival due to microbially delivered IL-22 were measured. Lactobacillus reuteri producing IL-22, or Escherichia coli-IL-22 were compared to determine which delivery system is better. Results C57BL/6 mice receiving IL-22 probiotics at 24 h after 9.25 Gy TBI, demonstrated green fluorescent protein-positive bacteria in the intestine, doubled the number of Lgr5+ intestinal stem cells, and increased 30-day survival. Bacteria were localized to the jejunum, ileum, and colon. Conclusion Second-generation probiotics appear to be valuable for mitigation of TBI, and radiation protection during therapeutic total abdominal irradiation.
16 citations
TL;DR: JJ-450 represents a new class of AR antagonists with therapeutic potential for CRPC, including those resistant to enzalutamide, and blocks AR recruitment to androgen-responsive elements and suppresses AR target gene expression.
Abstract: Reactivation of androgen receptor (AR) appears to be the major mechanism driving the resistance of castration-resistant prostate cancer (CRPC) to second-generation antiandrogens and involves AR overexpression, AR mutation, and/or expression of AR splice variants lacking ligand-binding domain. There is a need for novel small molecules targeting AR, particularly those also targeting AR splice variants such as ARv7. A high-throughput/high-content screen was previously reported that led to the discovery of a novel lead compound, 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(4-(2,3-dimethylphenyl)piperazin-1-yl)ethan-1-one (IMTPPE), capable of inhibiting nuclear AR level and activity in CRPC cells, including those resistant to enzalutamide. A novel analogue of IMTPPE, JJ-450, has been investigated with evidence for its direct and specific inhibition of AR transcriptional activity via a pulldown assay and RNA-sequencing analysis, PSA-based luciferase, qPCR, and chromatin immunoprecipitation assays, and xenograft tumor model 22Rv1. JJ-450 blocks AR recruitment to androgen-responsive elements and suppresses AR target gene expression. JJ-450 also inhibits ARv7 transcriptional activity and its target gene expression. Importantly, JJ-450 suppresses the growth of CRPC tumor xenografts, including ARv7-expressing 22Rv1. Collectively, these findings suggest JJ-450 represents a new class of AR antagonists with therapeutic potential for CRPC, including those resistant to enzalutamide.
13 citations
TL;DR: The data strongly suggest that silencing of PTPRT by promoter hypermethylation is an important mechanism of STAT3 hyperactivation and targeting STAT3 may be an effective approach for the development of new lung cancer therapeutics.
Abstract: Signal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor, is constitutively activated in lung cancer, but mutations in pathway genes are infrequent. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 and PTPRT loss-of-function represents one potential mechanism of STAT3 hyperactivation as observed in other malignancies. We determined the role of PTPRT promoter methylation and sensitivity to STAT3 pathway inhibitors in non-small cell lung cancer (NSCLC). TCGA and Pittsburgh lung cancer cohort methylation data revealed hypermethylation of PTPRT associated with diminished mRNA expression in a subset of NSCLC patients. We report frequent hypermethylation of the PTPRT promoter which correlates with transcriptional silencing of PTPRT and increased STAT3 phosphorylation (Y705) as determined by methylation-specific PCR (MSP) and real time quantitative reverse transcription (RT)-PCR in NSCLC cell lines. Silencing of PTPRT using siRNA in H520 lung cancer cell line resulted in increased pSTAT3Tyr705 and upregulation of STAT3 target genes such as Cyclin D1 and Bcl-XL expression. We show this association of PRPRT methylation with upregulation of the STAT3 target genes Cyclin D1 and Bcl-XL in patient derived lung tumour samples. We further demonstrate that PTPRT promoter methylation associated with different levels of pSTAT3Ty705 in lung cancer cell lines had selective sensitivity to STAT3 pathway small molecule inhibitors (SID 864,669 and SID 4,248,543). Our data strongly suggest that silencing of PTPRT by promoter hypermethylation is an important mechanism of STAT3 hyperactivation and targeting STAT3 may be an effective approach for the development of new lung cancer therapeutics.
12 citations
TL;DR: The aim of this study is to deepen the understanding of transporter inhibition by studying the molecular basis of ligand recognition by comparing the effect of 44 compounds on the active transport mediated by three ABC transporters and identifying amino acids in both P-gp and MRP2 that appear to be important for ligand Recognition.
Abstract: ATP-binding cassette (ABC)-transporters protect tissues by pumping their substrates out of the cells in many physiological barriers, such as the blood-brain barrier, intestine, liver, and kidney. These substrates include various endogenous metabolites, but, in addition, ABC transporters recognize a wide range of compounds, therefore affecting the disposition and elimination of clinically used drugs and their metabolites. Although numerous ABC-transporter inhibitors are known, the underlying mechanism of inhibition is not well characterized. The aim of this study is to deepen our understanding of transporter inhibition by studying the molecular basis of ligand recognition. In the current work, we compared the effect of 44 compounds on the active transport mediated by three ABC transporters: breast cancer resistance protein (BCRP and ABCG2), multidrug-resistance associated protein (MRP2 and ABCC2), and P-glycoprotein (P-gp and ABCB1). Eight compounds were strong inhibitors of all three transporters, while the activity of 36 compounds was transporter-specific. Of the tested compounds, 39, 25, and 11 were considered as strong inhibitors, while 1, 4, and 11 compounds were inactive against BCRP, MRP2, and P-gp, respectively. In addition, six transport-enhancing stimulators were observed for P-gp. In order to understand the observed selectivity, we compared the surface properties of binding cavities in the transporters and performed structure-activity analysis and computational docking of the compounds to known binding sites in the transmembrane domains and nucleotide-binding domains. Based on the results, the studied compounds are more likely to interact with the transmembrane domain than the nucleotide-binding domain. Additionally, the surface properties of the substrate binding site in the transmembrane domains of the three transporters were in line with the observed selectivity. Because of the high activity toward BCRP, we lacked the dynamic range needed to draw conclusions on favorable interactions; however, we identified amino acids in both P-gp and MRP2 that appear to be important for ligand recognition.
11 citations
TL;DR: JJ‐450 is developed as a novel AR antagonist with the potential to treat enzalutamide‐resistant castration‐resistant prostate cancer (CRPC) and the point mutation ARF876L was reported to be stimulated, instead of inhibited, by enzymes.
Abstract: Background Castration-resistant prostate cancer can develop resistance to enzalutamide because of androgen receptor (AR) point mutations, AR overexpression, constitutively active AR splice variants, and/or elevated intratumoral androgen synthesis. The point mutation ARF876L was reported to be stimulated, instead of inhibited, by enzalutamide, thus contributing to enzalutamide resistance. We have recently developed JJ-450 as a novel AR antagonist with the potential to treat enzalutamide-resistant castration-resistant prostate cancer (CRPC). Methods We employed several assays to determine the impact of JJ-450 and enzalutamide on prostate cancer cell lines expressing green fluorescent protein (GFP)-ARF876L . These assays include a prostate-specific antigen enhancer/promoter-based luciferase assay to determine AR transcriptional activity, a quantitative real-time polymerase chain reaction assay, and Western blot analysis to detect expression of AR-target genes at the messenger RNA and protein level, fluorescence microscopy to show AR subcellular localization, and a 5-bromo-2'-deoxyuridine assay to measure prostate cancer cell proliferation. Results As expected, enzalutamide inhibited wild-type (WT) AR but not ARF876L transcriptional activity in the luciferase assay. In contrast, JJ-450 inhibited both WT-AR and ARF876L transcriptional activity to a similar extent. Also, enzalutamide retarded androgen-induced nuclear import of GFP-AR, but not GFP-ARF876L , whereas JJ-450 retarded nuclear import of both GFP-AR and GFP-ARF876L . To further evaluate JJ-450 inhibition of ARF876L , we stably transfected C4-2 cells separately with GFP-AR or GFP-ARF876L . Enzalutamide inhibited endogenous AR-target gene expression in C4-2-GFP-ARWT , but not in the C4-2-GFP-ARF876L subline, whereas JJ-450 inhibited AR-target gene expression in both C4-2 sublines. More importantly, enzalutamide inhibited proliferation of C4-2-GFP-ARWT , but not of the C4-2-GFP-ARF876L subline, whereas JJ-450 inhibited proliferation of both C4-2 sublines. Conclusion JJ-450 inhibits enzalutamide-resistant ARF876L mutant nuclear translocation and function. Our findings suggest that JJ-450 and its analogs should be further developed to provide a potential new approach for the treatment of enzalutamide-resistant CRPC.
11 citations
TL;DR: In this in vitro assay, only HSP70 was required, along with its ATPase cycle and relevant cochaperones, for Ubr1-mediated ubiquitination, suggesting a possible model of triage in which efficiently folded proteins are spared, while slow-folding or nonfolding proteins are iteratively tagged with ubiquitin for subsequent degradation.
Abstract: Chaperones can mediate both protein folding and degradation. This process is referred to as protein triage, which demands study to reveal mechanisms of quality control for both basic scientific and translational purposes. In yeast, many misfolded proteins undergo chaperone-dependent ubiquitination by the action of the E3 ligases Ubr1 and San1, allowing detailed study of protein triage. In cells, both HSP70 and HSP90 mediated substrate ubiquitination, and the canonical ATP cycle was required for HSP70's role: we have found that ATP hydrolysis by HSP70, the nucleotide exchange activity of Sse1, and the action of J-proteins are all needed for Ubr1-mediated quality control. To discern whether chaperones were directly involved in Ubr1-mediated ubiquitination, we developed a bead-based assay with covalently immobilized but releasable misfolded protein to obviate possible chaperone effects on substrate physical state or transport. In this in vitro assay, only HSP70 was required, along with its ATPase cycle and relevant cochaperones, for Ubr1-mediated ubiquitination. The requirement for the HSP70 ATP cycle in ubiquitination suggests a possible model of triage in which efficiently folded proteins are spared, while slow-folding or nonfolding proteins are iteratively tagged with ubiquitin for subsequent degradation.
9 citations
TL;DR: FA mouse models are valuable for elucidating DNA repair pathways in cell and tissue responses to TBI, and the role of drugs that target distinct cell death pathways.
Abstract: Background/aim Radiation mitigator, GS-nitroxide, JP4-039, was evaluated for mitigation of total body irradiation (TBI) in Fanconi anemia (FA) Fancd2-/- (129/Sv), Fancg-/- (B6), and Fanca-/- (129/Sv) mice. Materials and methods JP4-039 dissolved in 30% 2-hydroxypropyl-β-cyclodextrin was injected intramuscularly 24 h after total body irradiation (9.25 Gy) into Fanca-/-, Fancd2-/- and Fancg-/- mice. Irradiation survival curves were performed in vitro using bone marrow stromal cell lines derived from Fanca-/-, Fancd2-/- and Fancg-/- mice. Results FA mice demonstrate genotype specific differences in TBI mitigation by JP4-039. Radiation effects in derived bone marrow stromal cell lines in vitro were mitigated by drugs that block apoptosis, but not necroptosis or ferroptosis. Conclusion FA mouse models are valuable for elucidating DNA repair pathways in cell and tissue responses to TBI, and the role of drugs that target distinct cell death pathways.
TL;DR: X-ray crystallography revealed that a potent, reversible, first-in-class small molecule inhibitor of the oncogenic phosphatase protein tyrosine phosphatases 4A3 binds to at least one site on human serum albumin, which is likely to extend the compound’s plasma half-life and thus assist in drug delivery into tumors.
Abstract: Protein tyrosine phosphatase (PTP) 4A3 is frequently overexpressed in human solid tumors and hematologic malignancies and is associated with tumor cell invasion, metastasis, and a poor patient prognosis. Several potent, selective, and allosteric small molecule inhibitors of PTP4A3 were recently identified. A lead compound in the series, JMS-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), has a long plasma half-life (∼ 24 hours) in mice, suggesting possible binding to serum components. We confirmed by isothermal titration calorimetry that JMS-053 binds to human serum albumin. A single JMS-053 binding site was identified by X-ray crystallography in human serum albumin at drug site 3, which is also known as subdomain IB. The binding of JMS-053 to human serum albumin, however, did not markedly alter the overall albumin structure. In the presence of serum albumin, the potency of JMS-053 as an in vitro inhibitor of PTP4A3 and human A2780 ovarian cancer cell growth was reduced. The reversible binding of JMS-053 to serum albumin may serve to increase JMS-053’s plasma half-life and thus extend the delivery of the compound to tumors. SIGNIFICANCE STATEMENT X-ray crystallography revealed that a potent, reversible, first-in-class small molecule inhibitor of the oncogenic phosphatase protein tyrosine phosphatase 4A3 binds to at least one site on human serum albumin, which is likely to extend the compound’s plasma half-life and thus assist in drug delivery into tumors.
TL;DR: Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington's disease.
Abstract: The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington's disease.
TL;DR: Findings suggest that the arsenic-activated mitochondrial EGFR pathway drives pathogenic signaling for impaired myoblast metabolism and function.
TL;DR: The fact that MMS-350 was effective at reducing pulmonary fibrosis induced by different triggers, the differential biological effects of its close structural analogues and its oral availability make it an attractive therapeutic candidate for organ fibrosis.
Abstract: Fibrosis is a common feature of several diseases, involves different organs, and results in significant morbidity and mortality. There are currently no effective therapies to halt the progression of fibrosis or reverse it. We have identified the highly water-soluble MMS-350, a novel bis-oxetanyl sulfoxide, as an antifibrotic agent. MMS-350 reduced the profibrotic phenotype induced in vitro in primary human fibroblasts and ameliorated bleomycin-induced pulmonary fibrosis in vivo. Furthermore, MMS-350 reversed fibrosis in human skin in organ culture. MMS-350 reduced levels of extracellular matrix proteins, the activation of fibroblasts, and the induction of pro-fibrotic factors. Similar effects at lower concentrations were observed with KRL507-031 and CL-613-091, two more lipophilic MMS-350 analogues. The fact that MMS-350 was effective at reducing pulmonary fibrosis induced by different triggers, the differential biological effects of its close structural analogues and its oral availability make it an attractive therapeutic candidate for organ fibrosis.
TL;DR: The cellular processes initiated by chemical injury to the endothelium barrier that result in cell toxicity; yet, inhibiting these processes does not necessarily protect BBB integrity which is regulated by the iron mediated HIF2α – Ve-cadherin axis.
Abstract: The blood-brain barrier (BBB) serves as the guardian of the CNS, tightly regulating the movement of ions, molecules, and cells between the circulatory system and brain. This barrier is critical in maintaining brain homeostasis, allowing proper neuronal function and protecting the brain from injury and disease. Chronic and acute exposure to various chemicals lead to BBB breakdown through pathways that are also affected in neurological diseases. Therefore, we have created an in-vitro BBB injury model to gain a better understanding of the mechanisms controlling BBB integrity. This model exposes a co-culture of human stem-cell derived brain-like endothelial cells (BLEC) and brain pericytes that mimic the BBB, to the organophosphate paraoxon. This exposure results in rapid lipid peroxidation, initiating a ferroptosis-like process and leading to endothelium cell toxicity. Mitochondrial ROS formation (MRF) and increase in mitochondrial membrane permeability (MMP), which occur 8 - 10 h post paraoxon-induced injury, also trigger apoptotic cell death. Yet, these processes do not directly result in damage to barrier functionality since blocking them does not reverse the increased permeability. Looking for a crucial pathway affecting barrier functionality we analyzed the iron homeostasis in our model since the iron chelator, Desferal© (DFO) rescued endothelial cell viability. Upon BBB insult, the liable iron pool (LIP) is rapidly increased, preventing the increased expression of the stress related hypoxia-induced factor 2α (HIF2α) transcription factor. This results in a decrease in surface expression of the adherens junction and permeability master regulator protein, Ve-cadherin, ultimately damaging BBB integrity. Unlike the apoptosis inhibitor ZVAD that rescues BLEC from cell toxicity, yet exacerbates damage to the barrier functionality, DFO significantly decreases MRF and apoptosis subsequent to PX exposure, while also rescuing barrier integrity by inhibiting the liable iron pool increase, inducing HIF2α expression and preventing the degradation of Ve-cadherin on the cell surface. Moreover, the novel nitroxide JP4-039 significantly rescues both injury-induced endothelium cell toxicity and barrier functionality. Collectively, we have elucidated the cellular processes initiated by chemical injury to the endothelium barrier that result in cell toxicity; yet, inhibiting these processes does not necessarily protect BBB integrity which is regulated by the iron mediated HIF2α – Ve-Cadherin axis. DFO protects BBB integrity by inhibiting the injury-induced deregulation of this axis. Additionally, we have discovered a novel compound, JP4-039, that inhibits both damage to endothelium functionality and cell toxicity. Elucidating a regulatory pathway that maintains BBB integrity and discovering both a novel and an FDA approved compound that interfere with this pathway elucidates a potential therapeutic approach to protect the BBB degradation that is evident in many neurological diseases.
TL;DR: This issue presents expert articles covering a wide diversity of topics from some of the most prominent and creative research groups, and addresses numerous therapeutic areas, such as autoimmune and inflammatory diseases, anxiety disorders, bacterial and viral infections, cancer, gout, ischemia, pain, metabolic disorders, chronic obstructive pulmonary disorder, asthma, rheumatoid arthritis, psoriasis, lysosomal storage disorders, and neurodegenerative diseases.
Abstract: T year, ACS Medicinal Chemistry Letters celebrates its 10th anniversary. To recognize this occasion, we are publishing a Special Issue entitled “Medicinal Chemistry: From Targets to Therapies”. Much has happened since our original call in July 2019 for contributions to this anniversary issue. Indeed, the coronavirus SARS-CoV has overtaken the world amidst a global pandemic. Consequently, antiviral research and vaccine development and production have been catapulted into the spotlight. In the face of the problem of viral and bacterial resistance, there is a pressing need for enhanced, sustained research on anti-infective agents. At the same time, pharmaceutical treatments in many other fields are still urgently needed. Medicinal Chemistry is called upon to answer gaps and inequalities in addressing public health needs, more than ever on a moment’s notice. We are honored to be able to present expert articles covering a wide diversity of topics from some of the most prominent and creative research groups. These papers address numerous therapeutic areas, such as autoimmune and inflammatory diseases, anxiety disorders, bacterial and viral infections, cachexia and anorexia, cancer, gout, ischemia, pain, metabolic disorders, chronic obstructive pulmonary disorder (COPD), asthma, rheumatoid arthritis, psoriasis, lysosomal storage disorders, and neurodegenerative diseases. Thirty-three Letters, two Viewpoints, three Innovations and three Patent Highlights have been contributed by prominent players in their respective fields. Letters cover subjects such as cyclooxygenase 1 detection (by Malerba et al.), FAK-targeting PROTACs (Gao et al.), a chimeric inhibitor of macrophage migration inhibitory factor (Cirillo et al.), Bruton’s tyrosine kinase (BTK) inhibitors (Zhang et al.), oximes for acetylcholine esterase reactivation (Gambino et al.), Zika virus inhibitors (Coluccia et al.), phosphodiesterase 4B (PDE4B) inhibitors (Vadukoot et al.), sirtuin 1−3 inhibition (Rajabi et al.), analogs of the Gram-negative antibiotic zafirlukast (Howard et al.), screens for hepatitis B (HBV) antiviral discovery (Hartman et al.), A3 adenosine receptor (A3AR) agonists (Tosh et al.), fibroblast growth factor receptor 4 (FGFR4) inhibitors (Liu et al.), inactivators of γ-aminobutyric acid aminotransferase (GABA-AT) (Shen et al.), bitopic agonists of dopamine D3R (Battiti et al.), 15 harmaline analogs as COX-2 inhibitors (Uddin et al.), imaging approaches in osteoarthritis (Uddin et al.), HIV-1 protease inhibitors (Ghosh et al.), brain-permeable tafamidis analogs (Sinha et al.), melanocortin receptor antagonists (Ericson et al.), choline antimetabolites (Bollenbach et al.), bromodomain and extra-terminal (BET) inhibitors (Altenburg et al.), raltegravir photoaffinity labels (Pala et al.), selective orexin-1 antagonists (Prev́ille et al.), folate receptor targeting agents (Jin et al.), intracellular peptide delivery (Ng et al.), gibberellin-based inhibitors of NF-kB (Annand et al.), agonists of a cannabinoid-activated GPCR (Schoeder et al.), ceramide galactosyltransferase enzyme inhibitors (Thurairatnam et al.), thermoresponsive perfluorocarbon hydrogels (Herneisey et al.), a sigma-2 receptor agonist that could be effective in COVID-19 (Colabufo et al.), a uric acid uptake inhibitor (Uda et al.), and cationic photosensitizers (Mazumdar et al.). A Featured Letter describes the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that can serve both as a tool compound as well as a lead structure for apoptosis-inducing anticancer drugs (Wang et al.). Viewpoints provide perspectives on isosteric replacements of anilines (Sodano et al.) and deuterium-switches (DeWitt et al.). Innovations demonstrate the utility of phenotypic drug discovery strategies (Childers et al.), allosteric modulators (Han et al.), and brain-penetrant EGFR tyrosine kinase inhibitors (Tsang et al.). The Patent Highlights discuss the development of dual specificity tyrosine phosphorylation regulated kinase-1 A (DYRK1A) inhibitors (Kargbo), a SMARCA2/4 PROTAC (Kargbo), and C-RAF and EGFR combination therapy (Kargbo). Our 10-year anniversary issue includes contributions from authors in Australia, China, Denmark, Germany, Italy, Japan, Poland, Singapore, Taiwan, and the USA, reflecting the truly international nature of contemporary Science. As an ensemble, these articles showcase the diversity and state-of-the-art of medicinal chemistry in 2020, as well as implications for future therapeutic developments. Bruce E. Maryanoff orcid.org/0000-0003-3590-2357 Peter Wipf orcid.org/0000-0001-7693-5863