Discovery of potent and selective CDK8 inhibitors through FBDD approach

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.     

Discovery of a novel class of 2-aminopyrimidines as CDK1 and CDK2 inhibitors

A series of new 2-(2-aminopyrimidin-4-yl)phenol derivatives were synthesized as potential antitumor compounds. Substitution with pyrrolidine-3,4-diol at the 4-position of phenol provided potent inhibitory activity against CDK1 and CDK2. X-ray crystal structural studies were performed to account for the effect of the substituent on both the enzymatic and cell growth inhibitory activities.     

Design and synthesis of novel imidazo[4,5-b]pyridine based compounds as potent anticancer agents with CDK9 inhibitory activity

New imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC₅₀ = 0.63–1.32 μM) relative to sorafenib (IC₅₀ = 0.76 μM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 where it revealed superior binding affinity relative to the natural ligand (T3C).     

Discovery of a potent and selective aurora kinase inhibitor

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.     

Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor

The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.     

Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode

A piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.     

Rational discovery of a highly novel and selective mTOR inhibitor

Aided by Structure Based Drug Discovery (SBDD), we rapidly designed a highly novel and selective series of mTOR inhibitors. This chemotype conveys exquisite kinase selectivity, excellent in vitro and in vivo potencies and ADME safety profiles. These compounds could serve as good tools to explore the potential of TORC inhibition in various human diseases.     

Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery

We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the ‘DFG-out’ conformation.     

Discovery of novel CDK inhibitors via scaffold hopping from CAN508

Cyclin-dependent kinases (CDKs) are promising drug targets for various human diseases, especially for cancers. Scaffold hopping strategy was applied on CAN508, a known selective CDK9 inhibitor, and a series of pyrazolo[3,4-b]pyridine compounds were synthesized and evaluated in vitro as CDK2 and CDK9 inhibitors. Most compounds exhibited moderate to potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems. Among them, compound 2e showed IC₅₀ values of 0.36?μM for CDK2 and 1.8?μM for CDK9, respectively. Notably, the scaffold alteration seems to cause a shift in the selectivity profile of the inhibitors. In contrast to CAN508, compound 2k demonstrated remarkable selectivity toward CDK2 (265-fold over CDK9). Docking studies on compound 2k provided hints for further design of more potent and selective CDK2/CDK9 inhibitors.     

Expression, purification, and circular dichroism analysis of human CDK9

The human cyclin-dependent kinase 9 (CDK9) protein was expressed in E. coli BL21 using the pET23a vector at 30 degrees C. Several milligrams of protein were purified from soluble fraction using ionic exchange and ATP-affinity chromatography. The structural quality of recombinant CDK9 and the estimation of its secondary structure were obtained by circular dichroism. Structural models of CDK9 presented 26% of helices in agreement with the spectra by circular dichroism analysis. This is the first report on human CDK9 expression in Escherichia coli and structure analysis and provides the first step for the development of CDK9 inhibitors.     

Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy

Novel acetyl-CoA carboxylase 2 (ACC2) selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and left part of the lead compound 1b improved the ACC2 inhibitory activity and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor 2e which showed in vivo efficacy in C57BL/6 mice.     

Withanone as an inhibitor of survivin: A potential drug candidate for cancer therapy

Survivin, the smallest inhibitor of apoptosis protein, which has been reported to be highly expressed in almost all known cancers, plays a dual role in survival as well as the proliferation of cancer cells. It inhibits apoptosis by inhibiting caspases as well as facilitating mitosis by becoming a part of chromosomal passenger complex through its BIR5 domain. Docking studies carried out with herbal ligand withanone derived from roots of Withania somnifera have shown strong binding affinity of −19.1088 kJ/mol with BIR5 domain of survivin and in turn interferes with inhibitory action against caspases and may lead to apoptosis. Binding of withanone at BIR5 domain of survivin may also interfere with chromosomal passenger complex and lead to halt the mitotic process within the cancer cell. Docking studies support various experimental outcomes and suggest withanone as a potential candidate molecule in cancer therapy.     

Discovery of HyT-Based Degraders of CDK9-Cyclin T1 Complex

Direct modulation of the non-kinase functions of cyclin and CDK-cyclin complexes poses challenges. We utilize hydrophobic tag (HyT) based small-molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. LL-CDK9-12 demonstrated the most potent and selective degradation ability, with DC₅₀ values of 0.362 μM against CDK9 and 0.680 μM against cyclin T1. In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader. Moreover, LL-CDK9-12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes′ degraders.     

Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure

The design of a novel series of cyclin-dependent kinase (CDK) inhibitors containing a macrocyclic quinoxaline-2-one is reported. Structure-based drug design and optimization from the starting point of diarylurea 2, which we previously reported as a moderate CDK1,2,4,6 inhibitor [J. Biol.Chem.2001, 276, 27548], led to the discovery of potent CDK1,2,4,6 inhibitor that were suitable for iv administration for in vivo study.     

Overview of CDK9 as a target in cancer research

CDK9 is a protein in constant development in cancer therapy. Herein we present an overview of the enzyme as a target for cancer therapy. We provide data on its characteristics and mechanism of action. In recent years, CDK9 inhibitors that have been designed with molecular modeling have demonstrated good antitumoral activity in vitro. Clinical studies of the drugs flavopiridol, dinaciclib, seliciclib, SNS-032 and RGB-286638 used as CDK9 inhibitors are also reviewed, with their additional targets and their relative IC₅₀ values. Unfortunately, treatment with these drugs remains unsuccessful and involves many adverse effects. We could conclude that there are many small molecules that bind to CDK9, but their lack of selectivity against other CDKs do not allow them to get to the clinical use. However, drug designers currently have the tools needed to improve the selectivity of CDK9 inhibitors and to make successful treatment available to patients.     

Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (−)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (−)-4a are described.     

Synthesis and biological evaluation of N9-cis-cyclobutylpurine derivatives for use as cyclin-dependent kinase (CDK) inhibitors

A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure–activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC₅₀ = 2.1 and 4.8 nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound 81 with CDK2 and CDK5.     

Discovery of novel spiro-piperidine derivatives as highly potent and selective melanin-concentrating hormone 1 receptor antagonists

Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC₅₀ value of 0.09 nM at hMCH-1R. The synthesis and structure–activity relationships of the novel spiro-piperidine MCH-1R antagonists are described.     

Discovery of 9-phenylacridinediones as highly selective butyrylcholinesterase inhibitors through structure-based virtual screening

Butyrylcholinesterase (BuChE) is considered a promising drug target as it plays an important role in the progression of late stage Alzheimer’s disease (AD). Two compound libraries were selected and 64 124 amine containing moieties were screened using a hierarchical virtual screening protocol to discover new selective BuChE inhibitors. From these and subsequent docking experiments, 9-phenylacridinedione (9-PAD) was identified as a promising scaffold for selective inhibition of BuChE. Selected top dock scored 9-PADs were assayed and compounds 3 and 6 exhibited potent and highly selective human BuChE inhibition (IC₅₀: 98 nM and 142 nM, respectively). Both molecules were also predicted to show sufficient brain permeability, not have any substantial toxicities, especially hepatotoxicity, and no significant in vitro cytotoxicity against SH-SY5Y neuroblastoma cells at concentrations up to 100 µM. These findings indicate that 9-PAD is a promising lead structure for the development of agents able to treat late stage AD.