September 29th<\/p>\n
https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.5c00887<\/a><\/p>\n Abstract<\/p>\n Here, we report our strategy to design an optimized oral selective estrogen receptor degrader (SERD), including human pharmacokinetics, by exploiting the bicyclo[1.1.1]pentane (BCP) ring system. The BCP has been shown to serve as a surrogate for phenyl rings and alkyl groups in drug candidates, reducing metabolism and improving physicochemical properties. It has not been extensively profiled in human clinical trials. We optimized a number of molecules and ultimately selected compound\u00a04,<\/b>\u00a0which showed excellent cell potency in breast cancer lines and displayed highly favorable in vitro ADME properties across multiple species. This translated into highly desired exposure in vivo across both rodent and nonrodent species exceeding that observed with other contemporary SERDs and downregulators. After fully profiling the compound, we nominated compound\u00a04<\/b>\u00a0(ZN-c5) for clinical development. Compound\u00a04<\/b>\u00a0advanced into Phase 1\/2 clinical trials, which demonstrated high human exposure upon dosing patients with 50 mg once a day.<\/p>\n <\/p>\n September 25th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.5c00323<\/a><\/p>\n Abstract<\/p>\n Tumor necrosis factor \u03b1 (TNF\u03b1) plays a critical role in inflammatory and autoimmune diseases. While biologic drugs have improved patient outcomes in conditions like rheumatoid arthritis by disrupting TNF\u03b1 signaling, small molecule targeting has been challenging due to the strong TNF-receptor binding and difficulty in disrupting the TNF trimer. This research presents small molecule TNF\u03b1 inhibitors with a novel bridged-piperazine core, developed through molecular dynamics simulation and scaffold hopping. The initial hit was optimized using structure-based design, leading to the discovery of a lead molecule with similar potency to the prototype but enhanced physicochemical properties. This lead demonstrated oral efficacy in a mouse glucose-6-phosphate isomerase-induced paw swelling model, comparable to the effects of a TNF\u03b1 antibody. The estimated effective human dose is 200 mg once daily, highlighting the potential for clinical development of these compounds.<\/p>\n <\/p>\n September 22nd<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.5c00294<\/a><\/p>\n Abstract<\/p>\n Dopamine replacement therapies for Parkinson\u2019s disease often produce dyskinesias with long-term use. Published studies suggest that introducing \u03b2-arrestin signaling might be protective for dyskinesia. We advanced known noncatecholamine D1\/D5 receptor G protein-biased agonists and found that removal of oxygen in the linker from published compounds limited \u03b2-arrestin recruitment, whereas introduction of nitrogen on the central\u00a0o<\/i>-phenyl linker favored \u03b2-arrestin recruitment and provided orally bioavailable compounds. Cryogenic electron microscopy suggested key receptor\u2013ligand interactions influencing the different bias behaviors. We discovered compound\u00a024<\/b>, a D1\/D5 receptor agonist with \u03b2-arrestin recruitment and properties for use\u00a0in vivo<\/i>. We compared\u00a024<\/b>\u00a0with tavapadon, which shows weak efficacy for \u03b2-arrestin signaling, in a rat model of Parkinson\u2019s disease with L-DOPA-induced dyskinesias. At particular doses, compound\u00a024<\/b>\u00a0produced efficacy comparable to L-DOPA, but with fewer concomitant dyskinesias. This first\u00a0in vivo<\/i>\u00a0study suggests that \u03b2-arrestin may have a positive influence on reducing dyskinesias following acute administration.<\/p>\n <\/p>\n September\u00a0 18th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.5c00695<\/a><\/p>\n Abstract<\/p>\n Casein kinase 2 (CK2) has emerged as a promising therapeutic target across a broad spectrum of malignancies, including pediatric and orphan cancers. The identification of a ligandable allosteric \u03b1D pocket on the CK2\u03b1 subunit has enabled the development of bivalent inhibitors, which bind simultaneously to both the adenosine triphosphate (ATP) site and the allosteric pocket. Here, we report the discovery and pharmacological characterization of\u00a0KDX1381<\/b>, a structure-guided bivalent CK2\u03b1 inhibitor with low-nanomolar potency and high selectivity, confirmed by cocrystal structures. In mice,\u00a0KDX1381<\/b>\u00a0suppressed CK2-driven tumor growth as a monotherapy and enhanced therapeutic efficacy when combined with vascular endothelial growth factor receptor (VEGFR) inhibitors or DNA-damaging agents in hepatocellular carcinoma and glioma models. These findings support bivalent CK2\u03b1 inhibition as a differentiated therapeutic strategy with broad applicability in CK2-dependent cancers.<\/p>\n September 15th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c03029<\/a><\/p>\n Abstract<\/p>\n A novel class of selective and potent WRN helicase antagonists identified via a DNA-encoded library screen was rigorously validated by various biophysical assays including ASMS, TSA, and SPR. Preliminary structure-activity-relationship studies identified the key pharmacophores and advanced the biochemical potency to single digit nanomolar. Potent analogs demonstrated anti-proliferative activities specifically in cell lines with a WRN genetic dependency. A crystal structure of a ligand-WRN complex revealed an unexpected large shift of the helicase domain compared to the apo WRN structure with ADP. These structural insights led to the successful design of covalent inhibitors and the identification of compound resistant WRN mutants that confirmed on-mechanism cellular activity. The covalent interaction between the ligand and at WRN Cys727 was confirmed by intact mass spectrometry and a bound crystal structure. The discovery of these unique WRN inhibitors provides more insight into the field and offers an opportunity to further optimize such molecules.<\/p>\n <\/p>\n September 11th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c02186<\/a><\/p>\n Abstract<\/p>\n Retinopathy of prematurity (ROP) blinds severely premature infants and is caused by oxygen supplementation. Hypoxia-inducible factor (HIF) stabilization during hyperoxia can prevent oxygen-induced retinopathy (OIR), the experimental correlate of ROP. Stabilization of hepatic HIF-1 alone can prevent OIR while contemporaneously protecting other organ systems, such as the lung and brain, from oxygen toxicity. However, HIF stabilization in central nervous system (CNS) oligodendrocytes reduces myelination. Here, we report the synthesis of small molecules specifically designed to not cross the blood-brain barrier based on a prodrug structure susceptible to hepatic carboxylesterases that release active drug. Twenty compounds were synthesized and rank ordered by Western blot, hypoxia response element binding, and reporter gene analysis. The lead compound prevented OIR, maintained normal CNS myelination, preserved the electroretinogram b-wave, and protected astrocytes. Strategies such as this might be broadly applicable to target specific hepatic functions while limiting off-target effects in other organs.<\/p>\n September 9th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.3c00034<\/a><\/p>\n Abstract<\/p>\n Although fragment-based drug discovery (FBDD) has been successfully implemented and well-explored for protein targets, its feasibility for RNA targets is emerging. Despite the challenges associated with the selective targeting of RNA, efforts to integrate known methods of RNA binder discovery with fragment-based approaches have been fruitful, as a few bioactive ligands have been identified. Here, we review various fragment-based approaches implemented for RNA targets and provide insights into experimental design and outcomes to guide future work in the area. Indeed, investigations surrounding the molecular recognition of RNA by fragments address rather important questions such as the limits of molecular weight that confer selective binding and the physicochemical properties favorable for RNA binding and bioactivity.<\/p>\n <\/p>\n September 5th<\/p>\nDiscovery of Orally Efficacious Bridged Piperazines as smTNF Modulators<\/span><\/h2>\n
Orally Bioavailable Dopamine D1\/D5 Receptor-Biased Agonists to Study the Role of \u03b2-Arrestin in Treatment-Related Dyskinesia in Parkinson\u2019s Disease<\/span><\/h2>\n
Discovery of KDX1381, a Bivalent CK2\u03b1 Inhibitor for the Treatment of Solid Tumors as a Single Agent or in Combination<\/span><\/h2>\n
Validation, Key Pharmacophores, and X-ray Cocrystal Structures of Novel Biochemically and Cellularly Active WRN Inhibitors Derived from a DNA-Encoded Library Screen<\/span><\/h2>\n
Characterization of Hepatotropic Small Molecule Inhibitors of Hypoxia Inducible Factor Prolyl Hydroxylase in the Prevention of Oxygen-Induced Retinopathy<\/span><\/h2>\n
Fragment-Based Approaches to Identify RNA Binders<\/span><\/h2>\n
Discovery of BAY 3389934 Hydrochloride: A Potent and Selective Small-Molecule Dual Factor IIa\/Xa Inhibitor with Short Half-Life for the Acute Treatment of Sepsis-Induced Coagulopathy<\/span><\/h2>\n