Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases (original) (raw)

Structure‐guided discovery of cyclin‐dependent kinase inhibitors

…, 2008

CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding ...

Identification of N -(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1 H -pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design †

Journal of Medicinal Chemistry, 2008

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

Identification of novel inhibitors against Cyclin Dependent Kinase 9/Cyclin T1 complex as: Anti cancer agent

Saudi Journal of Biological Sciences, 2017

Cell cycle consists of different types of phases, transition from G1, S, G2, M. Inhibition of associated CDKs like CDK9/Cyclin T1 complex, which are indirectly involved in the Cell cycle progression in the form of transcription elongation, reduces diverse diseases such as Cardiac Hypertrophy, Alzheimer's, Cancer, AIDS and Inflammation. Glide tool of the Schrodinger software has been used for performing Structure Based Virtual Screening and Docking against Drug Bank and MDPI database. The best hits were identified which go and bind in the active site of the target where ATP binds for the activity. The ADMET, MM-GBSA and DFT analysis is also done for the same. Compound 4-{4-[4-(3-aminopropoxy)phenyl]-1H-pyrazol-5-yl}-6-chlorobenzene-1,3-diol (DB08045) was found to be more potent, novel and selective as an inhibitor. Hopefully compound (DB08045) could be used as an anti-cancer agent for the treatment of life-threatening diseases.

4Alkoxy2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2

Bioorganic & Medicinal Chemistry Letters, 2003

The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC 50 vs cdk1/cyclinB1=2.9 AE 0.1 mM and IC 50 vs cdk2/cyclinA3=2.2 AE0.6 mM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclindependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy-or cycloalkoxy-groups at the O 4 -position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC 50 vs cdk1/ cyclinB1=12 AE2 mM and cdk2/cyclinA3=13 AE 4 mM) retaining significant activity. Substitutions at the N 6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC 50 vs cdk1/cyclinB1=35 AE3 mM and cdk2/cyclinA3=43 AE 3 mM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Å resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. #

Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile ( 7x ) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

Journal of Medicinal Chemistry, 2014

The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure−activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30−100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure−activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.

Structure-Based design of 2-Arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-Dependent kinases 1 and 2

Bioorganic & Medicinal Chemistry Letters, 2003

2 ABSTRACT An efficient synthesis of 2-substituted O 4 -cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure activity relationships (SARs) are similar to those observed for the corresponding O 6 -cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7s), were the most potent with IC 50 values of 0.7 ± 0.1 and 0.8 ± 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.

Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors

Molecules

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp3 carbon. All but one PKI pos...

Development of Highly Potent and Selective Diaminothiazole Inhibitors of Cyclin-Dependent Kinases

Journal of Medicinal Chemistry, 2013

Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC 50 = 0.0009-0.0015 µM) from a single hit compound with weak inhibitory activity (IC 50 = 15 µM), discovered by high-throughput screening. Structure-based design was performed using 35 co-crystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4 and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC 50 values between 0.27 and 6.9 µM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.