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Kinase Libraries

In spite of extensive studies on kinases as pharmacological targets during over last 20 years it still remains promising and efficient area in drug development paradigm. Kinases have proven their key roles in cancer, inflammation, diabetes and other diseases at the same time being the most convenient targets for drug development. Drugs such as Gleevec, Iressa, Tarceva, Sutent and other have shown high efficiency in treatment of various cancers without the negative side effects of traditional chemotherapy. Modulators of protein kinase activity are firmly established as a major class of drug targets for the pharmaceutical industry.

Kinase Hinge Region Directed Library

18 000 compounds

Based on our previous investigation and detailed structure analysis of the most known and most potent kinase inhibitors we have developed a series of unique structure filters aimed to identify potential inhibitors targeting ATP pocket. The standard kinase interaction pattern consists of a hydrogen bond acceptor for the hinge region, heteroaromatic core with different substituents and second hydrogen acceptor for the conserved Lysine residue. This type of inhibitors can be considered as ATP mimetics in the sense that they make interactions similar to what ATP makes. Bidentate H-bond that adenosine ring forms with hinge region is crucial for effective binding.

Analysis of a broad number of the kinase-inhibitor interactions has shown that at least two hydrogen bonds with the hinge region are necessary to exhibit high inhibitory potency. Molecular fragments able to form at least two hydrogen bonds with hinge region have been analyzed and appropriate topological models were developed for searching of directed inhibitors. The screening models were evaluated with reference set of known kinase inhibitors (over 2 000 molecules with high inhibitory activity).

Validated topological models were applied to 2.2 M Enamine stock collection to produce Kinase Hinge Region Directed Library (Fig. 1). Resulting set of compounds has been evaluated with main emphasis on novel chemotypes (Fig. 2). MedChem filters including PAINS and Ro5 molecular restriction were applied as prerequisite.

Examples of core structures and final compounds included in the Library Examples of core structures and final compounds included in the Library

Figure 1. Examples of core structures and final compounds included in the Library.

Selection of compounds bearing privileged scaffolds/moieties and bioisosteric core replacement was the key component of dedicated deign.

Figure 2. Selection of compounds bearing privileged scaffolds/moieties and bioisosteric core replacement was the key component of dedicated deign.

 

Aurora A Kinase Targeted Set

2 600 compounds

Our targeted library has been developed through iterative Virtual Screening – Synthesis – in vitro Validation strategy. Ultimate set of selected and specially synthesized molecules is an excellent source for lead discovery.

Features:

  • Comprises 2 601 compounds with 1 501 (57.7%) being newly synthesized
  • Complies with rigorous drug-like rules
  • Includes 12 scaffold series
  • Evaluated in vitro
  • Quality check
  • Exclusivity option

Library Design

Iterative design protocol included 6 rounds. In the first round Enamine stock collection was used as a source of compounds, whereas for other rounds new compounds were designed and synthesized.

Stock round
Docking technique has been applied against drug-like stock collection to disclose potential of the Enamine’s chemistry space. Careful selection from the docking complexes resulted in 1 100 compounds as initial Aurora A Targeted Set. In vitro validation by a mobility shift assay system at Carna Biosciences, Inc., Kobe, Japan, revealed 3 hit scaffold series.

De novo rounds
Based on generated in vitro data 5 rounds of design-synthesis-screening were performed. This approach allowed extending scaffold count to 12. These new rounds resulted in total 1 501 of newly synthesized compounds from the REAL database. Those compounds were evaluated using Aurora A kinase as a representative kinase at Carna. The assay revealed that the 336 compounds in the library presented 80% inhibition at 10µM and 26 compounds of them presented IC50 lower than 1µM.

Aurora A Kinase Focused Set Composition Image

Representation of general design of Aurora A Kinase Focused Set.

 

DYRK1A targeted Library

2 570 compounds, cherry-picking is available

Dual Specificity Tyrosine-Regulated Kinase 1a (DYRK1A) is an important component in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Although the inhibition of DYRK1A is a new strategy to modify the disease, very few inhibitors have been reported yet, and their potential clinical uses require further evaluation.

We designed DYRK1A focused Library basing on detailed investigation of known actives and their interaction with target protein. Accordingly to the reported data the main emphasis has been made on search of new ATP-pocket directed inhibitors. The library has been enriched with a fraction of compounds bearing new chemical cores and chemotypes selected via 3D pharmacophore searches to enhance probability of selective inhibitors finding.

Key Features of Library Design

  • All known PDB structures of DYRK1A have been examined (19 entries), superposition of most important features for ligand binding were used in query models composition and restriction constraints.
  • 4 Docking models have been selected for in silico screening and validated with appropriate series of known actives. Flexible docking algorithm was used.
  • 10 Ligand-based Pharmacophore models with shape constraints were evaluated and superimposed to yield 6 distinct pharmacophore performances within different binding modes.
  • MedChem filtered in-stock database was pre-proceeded with additional restriction and structural filters identified to be characteristic for kinase inhibitors.

Binding mode of hit obtained after docking calculation, 2VX3 PDB entry was used for model preparation.

Structures of known DYRK1A inhibitors used for ligand-based Pharmacophore models creation

Structure

Activity, IC50

Structure

Activity, IC50

155 nM 62 nM
340 nM 1.0 μM
1.1 μM 1.1 μM
342 nM 320 nM
320 nM 1.3 μM
9.6 μM 900 nM

Example of pharmocophore model with reference ligand (left A.) and hits-match obtained after calculations (right B).

A B

Pharmacophore model #4 built basing on CHEMBL3094449 structure (IC50 = 342 nM). 

 

DYRK1B, DCLK1 and c-Src Focused Sets

3 200 compounds Dyrk1B Set
2 300 compounds DCLK1 Set
1 200 compounds c-Src Set

Target sets are available as powders, dry films or DMSO solutions. All compounds have a minimum purity of 90% assessed by 1H NMR and LC-MS; analytical data are provided.



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