We herein describe the development and application of a modular technology platform which incorporates recent advances in plate-based microscale chemistry, automated purification, in situ quantification, and robotic liquid handling to enable rapid access to high-quality chemical matter already formatted for assays. In using microscale chemistry and thus consuming minimal chemical matter, the platform is not only efficient but also follows green chemistry principles. By reorienting existing high-throughput assay technology, the platform can generate a full package of relevant data on each set of compounds in every learning cycle.
View Article and Find Full Text PDFBoronic acids are essential building blocks used for the synthesis of bioactive molecules, the generation of chemical libraries and the exploration of structure-activity relationships. As a result, more than ten thousand boronic acids are commercially available. Medicinal chemists are therefore facing a challenge; which of them should they select to maximize information obtained by the synthesis of new target molecules.
View Article and Find Full Text PDFThe Myb transcription factor is involved in the proliferation of hematopoietic cells, and deregulation of its expression can lead to cancers such as leukemia. Myb interacts with various proteins, including the histone acetyltransferases p300 and CBP. Myb binds to a small domain of p300, the KIX domain (p300), and inhibiting this interaction is a potential new drug discovery strategy in oncology.
View Article and Find Full Text PDFStructures of the large majority of bioactive molecules are composed of several rings that are decorated by substituents and connected by linkers. While numerous cheminformatics studies focusing on rings and substituents are available, practically nothing has been published about the third important structural constituent of bioactive molecules - the linkers. The current study attempts to fill this gap.
View Article and Find Full Text PDFAnalysis of structure-activity data from a large corpus of medicinal chemistry literature identified a set of ring replacements that have a significant chance of improved biological activity. A database of these replacements for 245 common heterocyclic rings is provided. Based on the analysis of the whole data set, 80 diverse substituted rings are suggested for use in an early stage of hit optimization and in the design of focused libraries with the goal to explore structure-activity relationships and quickly improve the biological activity of the explored series.
View Article and Find Full Text PDFMALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series.
View Article and Find Full Text PDFThe concept of functional groups (FGs), sets of connected atoms that can determine the intrinsic reactivity of the parent molecule and in part are responsible for the overall properties of the molecule, form a foundation within modern medicinal chemistry. In this Article, we analyze the occurrence of various FGs in molecules described in the medicinal chemistry literature over the last 40 years and show how their development and utilization over time has varied. The popularity of various FGs has not evolved randomly, but instead, clear patterns of use are evident.
View Article and Find Full Text PDFThe serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa.
View Article and Find Full Text PDFBased on the similarity between the active sites of the deubiquitylating and deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionarily related protease adenain, a target-hopping screening approach on a focused set of adenain inhibitors was investigated. The cyanopyrimidine-based inhibitors identified represent the first active-site-directed small-molecule inhibitors of Cdu1. High-resolution crystal structures of Cdu1 in complex with two covalently bound cyanopyrimidines, as well as with its substrate ubiquitin, were obtained.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
January 2017
CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode.
View Article and Find Full Text PDFThe COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs.
View Article and Find Full Text PDFAdenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target.
View Article and Find Full Text PDFThe cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2.
View Article and Find Full Text PDFA series of novel benzimidazole derivatives has been designed via a scaffold morphing approach based on known calcilytics chemotypes. Subsequent lead optimisation led to the discovery of penta-substituted benzimidazoles that exhibit attractive in vitro and in vivo calcium-sensing receptor (CaSR) inhibitory profiles. In addition, synthesis and structure-activity relationship data are provided.
View Article and Find Full Text PDFParathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged.
View Article and Find Full Text PDFStarting from the purine lead structure 1, a new series of cathepsin K inhibitors based on a pyrimidine scaffold have been explored. Investigations of P3 and P2 substituents based on molecular modeling suggestions resulted in potent cathepsin K inhibitors with an improved selectivity profile over other cathepsins.
View Article and Find Full Text PDFA series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure 1 (Cbz-Leu-NH-CH2-CN, IC50 = 39 nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties.
View Article and Find Full Text PDFStarting from the high-throughput screening hit 1a, novel cathepsin K inhibitors have been developed based on a purine scaffold. High-resolution X-ray structures of several derivatives have revealed the binding mode of these unique cysteine protease inhibitors.
View Article and Find Full Text PDFModeling, synthesis and in vitro activities of a series of arylaminoethyl amide based inhibitors of the cysteine protease cathepsin K are described.
View Article and Find Full Text PDFJ Chromatogr B Analyt Technol Biomed Life Sci
April 2003
Cathepsin K is a cysteine proteinase, primarily expressed in osteoclasts, which has a strong collagenolytic activity and plays an essential role involved in bone matrix degradation. Its inhibition could provide a novel approach to the treatment and prevention of osteoporosis. One structural class of lead compounds in our cathepsin K inhibitors program is based on an arylaminoethyl amide scaffold, which has potential metabolic weak points that might be stabilized by appropriate chemical modification(s).
View Article and Find Full Text PDF5-Aryl-pyrrolo[2,3-d]pyrimidines incorporating different N(7)-substituents have been prepared and evaluated for their inhibitory potency towards the tyrosine kinase c-Src. Optimization of these compounds resulted in highly potent c-Src inhibitors, some (e.g.
View Article and Find Full Text PDFA series of N(alpha)-benzyloxycarbonyl- and N(alpha)-acyl-L-leucine(2-phenylaminoethyl)amide derivatives were prepared and evaluated for their inhibitory activity against rabbit and human cysteine proteases cathepsins K, L, and S. These data indicate that N(alpha)-acyl-alpha-amino acid-(arylaminoethyl)amides represent a new class of selective non-covalent inhibitors of cathepsin K. Compounds 4b, 4e, and 4g exhibit high potency toward rabbit and human cathepsin K (IC(50) < 0.
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