Ubiquitin-specific proteases (USPs) are crucial regulators of protein degradation pathways, influencing diverse cellular processes and disease mechanisms. Among them, USP30 plays a pivotal role in mitochondrial quality control and has been implicated in idiopathic pulmonary fibrosis (IPF), a chronic lung disease for which current therapies merely slow disease progression. The high flexibility of USP30’s catalytic site, coupled with its dependence on covalent interaction with the catalytic cysteine presents significant challenges in discovering suitable small molecule inhibitors. In this study, we identified three non-covalent small molecule inhibitors for USP30 using molecular modeling, X-ray crystallography, and virtual screening. These findings offer valuable insights and novel chemical starting points for further medicinal chemistry optimization.

A versatile method to access differentially substituted 1,3- and 1,4-diamines via a nickel-catalyzed three-component 1,2-carboamination of alkenyl amines with aryl/alkenylboronic ester nucleophiles and N–O electrophiles is reported. The reaction proceeds efficiently with free primary and secondary amines without needing a directing auxiliary or protecting group, and is enabled by fine-tuning the leaving group on the N–O reagent. The transformation is highly regioselective and compatible with a wide range of coupling partners and alkenyl amine substrates, all performed at room temperature. A series of kinetic studies support a mechanism in which alkene coordination to the nickel catalyst is turnover-limiting.

An alcohol-directed, nickel-catalyzed three-component umpolung carboamination of unactivated alkenes with aryl/alkenylboronic esters and electrophilic aminating reagents is reported. This transformation is enabled by specifically tailored O-(2,6-dimethoxybenzoyl)hydroxylamine electrophiles that suppress competitive processes, including undesired β-hydride elimination and transesterification between the alcohol substrate and electrophile. The reaction delivers the desired 1,2-carboaminated products with excellent regio- and diastereoselectivity and exhibits a broad scope of coupling partners and alkenes, including complex natural products. Various mechanistic experiments and analysis of the stereochemical outcome with a cyclic alkene substrate, as confirmed by X-ray crystallographic analysis, support alcohol-directed syn-insertion of an organonickel(I) species.

Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved single-digit nanomolar potency against both wild-type and mutant ABL kinases, especially ABL T315I bearing the gatekeeper residue mutation. We show that, by using techniques including mass spectrometry, time-dependent biochemical assays and X-ray crystallography, the evolutionarily conserved lysine can be targeted selectively. Furthermore, we show that the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate potential off-targets of our compounds at proteome-wide level in different cancer cell lines.

AXL is a member of the TAM (TYRO3, AXL, MER) subfamily of receptor tyrosine kinases. It is upregulated in a variety of cancers and its overexpression is associated with poor disease prognosis and acquired drug resistance. Utilizing a fragment-based lead discovery approach, a new indazole-based AXL inhibitor was obtained. The indazole fragment hit 11, identified through a high concentration biochemical screen, was expeditiously improved to fragment 24 by screening our in-house expanded library of fragments (ELF) collection. Subsequent fragment optimization guided by docking studies provided potent inhibitor 54 with moderate exposure levels in mice. X-ray crystal structure of analog 50 complexed with the I650M mutated kinase domain of Mer revealed the key binding interactions for the scaffold. The good potency coupled with reasonable kinase selectivity, moderate in vivo exposure levels, and availability of structural information for the series makes it a suitable starting point for further optimization efforts.

[This corrects the article DOI: 10.1021/acsmedchemlett.9b00170.].

Bacterial tRNA modification synthesis pathways are critical to cell survival under stress and thus represent ideal mechanism-based targets for antibiotic development. One such target is the tRNA-(N1G37) methyltransferase (TrmD), which is conserved and essential in many bacterial pathogens. Here we developed and applied a widely applicable, radioactivity-free, bioluminescence-based high-throughput screen (HTS) against 116350 compounds from structurally diverse small-molecule libraries to identify inhibitors of Pseudomonas aeruginosa TrmD (PaTrmD). Of 285 compounds passing primary and secondary screens, a total of 61 TrmD inhibitors comprised of more than 12 different chemical scaffolds were identified, all showing submicromolar to low micromolar enzyme inhibitor constants, with binding affinity confirmed by thermal stability and surface plasmon resonance. S-Adenosyl-l-methionine (SAM) competition assays suggested that compounds in the pyridine-pyrazole-piperidine scaffold were substrate SAM-competitive inhibitors. This was confirmed in structural studies, with nuclear magnetic resonance analysis and crystal structures of PaTrmD showing pyridine-pyrazole-piperidine compounds bound in the SAM-binding pocket. Five hits showed cellular activities against Gram-positive bacteria, including mycobacteria, while one compound, a SAM-noncompetitive inhibitor, exhibited broad-spectrum antibacterial activity. The results of this HTS expand the repertoire of TrmD-inhibiting molecular scaffolds that show promise for antibiotic development.

SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

Often, proteins belonging to the same family elicit distinct downstream bioactivities yet tend to have similar substrate/cofactor binding pockets with high sequence conservation.This makes it challenging for selective binding of small molecules to protein of interest during drug development.In order to better understand the dynamics of small molecule binding in homologous proteins, we did a structural comparative study of Smyd-small molecule complexes.Smyd (1-5) proteins are members of the protein methyltransferase family containing conserved SET and Zinc-finger MYND domains.In vivo, Smyd2 is known to methylate histone H3 and p53 and Smyd3, on the other hand, methylates histone H3 and MAP3 Kinase2.Overexpression of Smyd2 has been reported in esophageal squamous primary carcinomas and Smyd3 is overexpressed in colorectal and hepatocellular carcinoma.Bay-598 is a substrate competitive probe of Smyd2 with >100-fold selectivity over other histone methyltransferases.Smyd3-Bay598 complex structure reveals a binding pocket that is similar to Smyd2.X-ray crystal structure of Smyd3-Bay598 complex along with biophysical studies was performed to dissect the structural basis for the high selectivity of Smyd2 to Bay-598.

A simple method to convert readily available carboxylic acids into sulfinate salts by employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent, TFCS-Na. The reactivity of six of these salts towards C-H functionalization was field-tested using several different classes of heterocycles.

Upon several tested tertiary amines quinine shows to be the best promoter for the asymmetric aziridination of α,β-unsaturated ketones.

trans-N-Unsubstituted aziridines were synthesised (up to 77% ee) via a chiral tertiary amine-promoted nucleophilic aziridination of α,β-unsaturated ketones utilising in situ generated N–N ylides (aminimines). A wide range of chiral tertiary amines were synthesised and evaluated, allowing structure–activity relationships to be drawn. The most efficient promoter for asymmetric aziridination, quinine, was assessed with several enones to ascertain the effect of substrate structure on product ee, while the intermediate hydrazinium salt was characterised by X-ray crystallography.

A simple method for direct C-H imidation is reported using a new perester-based self-immolating reagent and a base-metal catalyst. The succinimide products obtained can be easily deprotected in situ (if desired) to reveal the corresponding anilines directly. The scope of the reaction is broad, the conditions are extremely mild, and the reaction is tolerant of oxidizable and acidlabile functionality, multiple heteroatoms, and aryl iodides. Mechanistic studies indicate that ferrocene (Cp2Fe) plays the role of an electron shuttle in the decomposition of the perester reagent, delivering a succinimidyl radical ready to add to an aromatic system.

Terpene cyclase phase: Inspired by this logic, a scalable and enantioselective divergent synthesis of germacrane-type sesquiterpenes is developed. Salient features of this work include: 1) the direct ring closure of a farnesol derivative to the 10-membered carbocycle 1, and 2) subsequent synthetic operations on 1 to gain access to different bicyclic frameworks such as guaianes, cadinanes, selinanes, and elemenes.

Solving the puzzles: Total synthesis played a key role in the elucidation of the stereochemistry and verification of the constitution of the complex polymeric natural product psychotetramine. The route features three powerful assembly processes that enabled four rounds of total synthesis-guided structure determination. The pursuit of this alkaloid also led to an improved procedure for indole–aniline coupling and a highly efficient enantioselective synthesis of psychotrimine. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.