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Targeted protein degradation (TPD) via proteolysis-targeting chimeras (PROTACs) is a powerful therapeutic strategy, yet only a small fraction of the >600 human E3 ligases have been harnessed. To expand this repertoire, we developed clickable photoaffinity probes based on clinically used drugs and metabolites to identify potential E3 ligases as targets. Here, we report the discovery of clofibric acid with a molecular weight of only 214 Da as a ligand for synoviolin (SYVN1). We demonstrate its utility by developing clofibric acid-based BRD4 PROTACs. The linker length and architecture play a critical role in the target degradation efficiency. The clofibric acid-derived BRD4 PROTACs achieve selective BRD4 degradation in an SYVN1-dependent manner. Our findings establish clofibric acid as a robust addition to the TPD toolbox, offering a novel E3 ligase recruitment strategy for the development of next-generation degraders.

Bone marrow tyrosine kinase gene in chromosome X protein (BMX) plays a critical role in the initiation, progression, and development of castration-resistant prostate cancer. While several ATP-competitive BMX inhibitors have been developed as cellular chemical tools to investigate the function of BMX, they are unable to target the nonenzymatic roles of BMX. Proteolysis-targeting chimeras (PROTACs) represent an emerging technology that enables the rapid and complete degradation of target proteins. Here, we describe the design, synthesis, and characterization of BMX PROTACs by conjugating the BMX and cereblon (CRBN) ligands. In LNCaP clone FGC cells, the representative compound 10c (IHMT-BMX-068) induced time- and dose-dependent BMX degradation with nanomolar DC50 values, a process mediated by the CRBN pathway and the proteasome system. It exhibited potent antiproliferative effects on prostate cancer cells. These results indicate that BMX-PROTACs are potential therapeutic candidates for prostate cancer.

Epstein-Barr nuclear antigen 1 (EBNA1) is an essential viral DNA-binding protein required for maintenance of Epstein-Barr virus (EBV) episomes and is expressed in all EBV-associated malignancies, making it an attractive therapeutic target. Using fragment-based screening and X-ray crystallography, we identified a 2,3-disubstituted benzoic acid scaffold that binds at the EBNA1 DNA-binding interface. Structure-guided optimization revealed that the carboxylic acid pharmacophore engages Asn519 and Thr590, while electron-rich heterocycles are positioned between Lys477 and Lys586, forming a cation-π-cation "lysine sandwich" that drives potency. Iterative medicinal chemistry improved binding affinity and physicochemical stability, leading to compound 35 (VK-2019), a submicromolar EBNA1 to DNA binding inhibitor. Compound 35 demonstrated favorable drug-like properties and robust antitumor efficacy in EBV-positive xenograft models and has advanced to clinical evaluation. These studies define the structural determinants of EBNA1 inhibition and establish a framework for targeting viral genome-maintenance proteins with small molecules.

Polo-like kinases (PLKs) are a family of closely related serine/threonine kinases responsible for regulating cell cycle processes and proliferation. While PLK1 inhibitors have led to clinical candidates for oncology, the biological function of other PLKs is relatively unknown, in part, because there is a dearth of selective tool compounds. Herein we report the parallel medicinal chemistry (PMC) and structure-assisted discovery of potent and selective PLK3 inhibitors with favorable drug-like properties. We employed computational tools to reveal subtly different pharmacophore features within homologous binding sites of PLKs. These preferences were then exploited via a PMC approach starting from in-house high-throughput screening hits, resulting in selective chemical probes that help elucidate the complexities of PLK biology. Further, by profiling compounds with a spectrum of PLK selectivities, our work demonstrates the relationship between inhibition of specific PLK isoforms and resulting toxicities.

We have conceptualized and executed an efficient, eco-friendly, one-flask, synthetic approach to functionally enriched and potentially pharmacophoric tetracyclic indenodiazepinones through a base-mediated reaction cascade involving Schiff base formation, intramolecular aza-Michael addition, and Mannich reaction between o-formylynones and o-phenylenediamines, rapidly generating a diverse library poised for exploring their therapeutic potential and medicinal chemistry applications. This operationally simple, no-waste protocol, embodying many green and sustainable features, has been scoped with 26 varied examples. The newly accessed indenodiazepinones exhibited promising preliminary antibacterial activity against Salmonella Typhimurium (STM). Interestingly, one of the compounds, 3v, did not develop resistance in STM upon repeated exposure to sublethal doses up to the 160th cycle, whereas resistance against the clinically used antibacterial ciprofloxacin began emerging from the 32nd cycle and became significant by the end of the 128th cycle. These preliminary findings open avenues for developing novel antimicrobial agents with enhanced durability against drug resistance, as disclosed in this study.

Semisynthetic modification of mycothiazole (1) with Meerwein's salt to generate a more stable and/or potent analog than 8-O-acetylmycothiazole (2) unexpectedly yielded diastereomers devoid of the diene. Analysis of NMR, HR-LCMS, and optical rotation confirmed the structures as (-)-4,4-hydroxy-methyl-(5Z)-(8S)-(14Z)-mycothiazole (5a, 5b: dr 1:1.1). Both compounds demonstrated reduced stability versus 1 or 2. Cytotoxicity evaluation of 5a versus 5b indicated 5-fold differences in potency against pancreatic (IC50 = 7.81, 1.34 μM; PANC-1) and glioblastoma (IC50 = 8.53, 1.63 μM; U251N) cancer cells, respectively. In vivo evaluation of 5a and 5b, using Caenorhabditis elegans in aging studies, indicated 5b not 5a inhibited mitochondrial function, while neither affected lifespan compared to 1. These results demonstrate the diene of 1 may be required for its picomolar cytotoxic potency to cancer cells or effects on lifespan in C. elegans, and minor variations in the stereochemistry of this chemotype merit further investigation to modulate its bioactivity.

[This corrects the article DOI: 10.1021/acsmedchemlett.9b00191.].

E1A-binding proteins p300 (EP300) and CREB-binding protein (CBP) are two homologous multidomain enzymes that have emerged as promising therapeutic targets in oncology. Recent drug discovery efforts have yielded degraders that target EP300/CBP by engaging either the bromodomain or the histone acetyltransferase (HAT) domain, with the latter potentially leading to preferential or selective degradation of one paralog. Building on a potent proline-based EP300/CBP HAT domain inhibitor, we designed, synthesized, and characterized a series of novel HAT-targeting and cereblon-recruiting proteolysis-targeting chimeras (PROTACs). In particular, compound 25a was identified as a PROTAC that promotes preferential degradation of EP300 over CBP, highlighting the potential of HAT domain engagement to modulate paralog selectivity. Functional studies in REH cells showed that preferential EP300 degradation by 25a resulted in impaired proliferation, G1 cell cycle arrest, and induction of apoptosis. Thus, HAT-targeting degrader 25a provides a promising foundation for further optimization toward therapeutic applications in EP300-dependent malignancies.

We describe the synthesis and biochemical characterization of a series of compounds derived from a previously reported pyrazolopyrimidine-based KRAS inhibitor [ACS Omega2019, 4 (2), 2921-2930]. Dozens of derivatives were made primarily by modifying the substituents of the pyrazolo-pyrimidine core with the goal of increasing binding affinity to KRAS and improving inhibitory activities against wild-type and oncogenic mutants of KRAS using biophysical measurements and cell proliferation assays. We show that while many of the new compounds exhibited a dramatic increase in binding affinity to KRAS, in many cases, that did not translate into improved potency in inhibiting cell growth. Considering the high binding affinities (up to single-digit nanomolar) and low micromolar inhibitory activities across multiple KRAS mutant cancer cells, we propose that these new derivatives will serve as useful investigational agents for KRAS studies or as starting points for further derivatization and structure-activity relationship studies.

[This corrects the article DOI: 10.1021/acsmedchemlett.6c00070.].

Nitazoxanide-based analogues were synthesized and evaluated for HBx-DDB1 interaction inhibition using a split-luciferase assay. Compared to the nitazoxanide (NTZ, IC50 = 1.2 μM) the compound 49a exhibited potent inhibition of the HBx-DDB1 interaction with an IC50 of 0.083 μM. Consistent with its HBx-DDB1 inhibitory effect, compound 49a showed antiviral activity in HBV-infected cells. Compound 49a displayed excellent metabolic stability in human liver microsomes (82% remaining after 30 min), minimal hERG inhibition, and limited CYP interference, showing only moderate inhibition of CYP2C9. In vivo pharmacokinetic studies in mice and rats revealed rapid absorption (T max = 0.5-3.5 h), low systemic clearance (0.09-0.10 L/h/kg), and high oral bioavailability (>90%). These findings establish compound 49a as a promising lead for the development of direct-acting antivirals targeting chronic HBV infection.

The rise in drug-resistant Mycobacterium tuberculosis (M.tb) necessitates new therapeutic strategies. Hypothesizing that a single compound targeting multiple M.tb proteins would make resistance less likely to evolve, we focused on identifying a single compound targeting multiple M.tb OmpR family two-component response regulators (RRs). We screened ∼8000 FDA-approved DrugBank compounds using computational tools (active-site prediction, receptor-ligand docking, and molecular dynamics simulations) to identify one compound acting on M.tb RRs: MtrA, PrrA, MprA, RegX3, and PhoP. Cefpiramide showed strong docking scores and favorable interactions with all five RRs. Experimental validations confirmed that cefpiramide binds MtrA and RegX3 with K b values of 109.69 ± 27.99 nM-1 and 113.49 ± 36.63 nM-1, respectively. Further, the disruption of transcription repressor function of MtrA is possibly by disruption of its DNA binding property, as mutant analysis indicated that cefpiramide targets the DNA-binding domain of MtrA. Cefpiramide inhibited M.tb H37Rv growth (MIC50 = 4 ± 2.38 μg/mL), warranting further investigation as a component of combinatorial tuberculosis therapy.

This patent describes heterocyclic carboxamindes as new, highly effective α2C-Adrenergic receptor (α2C-AR) antagonists, suitable for treating α2C-ARs-associated disorders. It offers detailed information on the heterocyclic carboxamindes, pharmaceutical formulations, and their applications in managing α2C-ARs-related conditions.

Provided herein are novel pyrrolidinone derivatives as SARM1 inhibitors, pharmaceutical compositions, use of such compounds in treating axonal degeneration, and processes for preparing such compounds.

Provided herein are novel 5,6-bicyclic compounds as 5-HT2A receptor agonists, pharmaceutical compositions, use of such compounds in treating depression, anxiety, substance abuse and headaches, and processes for preparing such compounds.

The G-protein-coupled receptor 35 (GPR35) plays a key role in various physiological and pathological processes and has emerged as a potential therapeutic target for the treatment of pain, inflammation, and metabolic diseases. Herein, we report the discovery and characterization of dantrolene analogues as GPR35 ligands. Pharmacological profiling with label-free dynamic mass redistribution and Tango arrestin assays showed that the 2,4-imidazolidinedione-containing analogues of dantrolene act as partial agonists of the GPR35, while its urea, thiourea, or amido derivatives display probe and assay dependent antagonism against the receptor.

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) drives colorectal cancer progression by promoting cell proliferation, inhibiting apoptosis, and facilitating angiogenesis, making STAT3 a highly promising therapeutic target. In this study, a series of juglone-based quinone derivatives were designed, synthesized, and systematically evaluated as STAT3 inhibitors. Among them, compound YZZ-24 exhibited the strongest STAT3 binding affinity (K i = 0.26 μM), which was significantly superior to juglone (K i = 17.11 μM). Mechanistic studies revealed that YZZ-24 directly binds to STAT3 and effectively inhibits STAT3 phosphorylation at tyrosine 705 (p-STAT3Tyr705) and STAT3 phosphorylation at serine 727 (p-STAT3Ser727), thereby blocking downstream oncogenic signaling with minimal effects on upstream kinases. Cellular functional assays demonstrated that YZZ-24 exerts potent antitumor activity against colorectal cancer cells (IC50 = 1.03 μM) and possesses an acceptable safety window (SI = 10.82). Collectively, YZZ-24 is a promising STAT3 inhibitor for the treatment of colorectal cancer.

Amino-acid-derived arylpropionamide androgen receptor (AR) modulators, termed EPic AR modulators, have been developed through an efficient 2-3 step synthesis from commercially available enantioenriched amino acid starting materials. This modular route delivers gram-scale quantities of the targets in excellent yield and with high enantiomeric excess (>99% ee), overcoming limitations in the enantioselective preparation of selective androgen receptor modulators (SARMs) and antiandrogens (AAs) while unlocking the previously invariant α-amido heteroatom for structural diversification. Binding assays reveal strong AR affinity for several analogs. Initial validation through cellular reporter assays demonstrates tunable antagonism, with select compounds exhibiting a distinctive biphasic profile: low-efficacy partial agonism at low concentrations that transitions to antagonism at higher doses. These results establish a powerful, operationally simple platform for the rapid generation of stereochemically defined AR modulators, offering new opportunities for next-generation therapeutics in muscle-wasting disorders, oncology supportive care, and androgen-related diseases.

High-throughput screening (HTS) and DNA-encoded library (DEL) selection are cornerstones of drug discovery but suffer from high operational infrastructure requirements or constraints to affinity-only selections. Herein we report a robust on-DNA compound screening method that bridges this gap, enabling direct functional evaluation of DNA-linked small molecules while bypassing plate-based or selection-wash limitations. To validate this platform, a focused collection of trisubstituted benzamides was synthesized and screened directly on-DNA against p38α MAPK. This methodology rapidly prioritized advanced structures, culminating in the seamless identification of compound I-13. Upon off-DNA synthesis, I-13 was confirmed as a potent p38α inhibitor (IC50 = 65 nM), demonstrating 4-fold selectivity over p38β and excellent selectivity over p38γ and p38δ (>461 fold). While achieving reasonable p38α/β isoform selectivity remains a subject for future optimization, this platform offers a powerful, low-barrier alternative to traditional HTS and DEL for rapid, functional hit-to-lead discovery.