The association between anti-tumor potency and structure-activity of protein-kinases inhibitors based on quinazoline molecular skeleton

<div> <p>Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compounds displayed <i>K</i><sub>D</sub> values of 190 nM and 401 nM for VRK1 and VRK2, respectively. Differences in compound binding mode and substituent preferences between the two VRKs were identified by the series structure-activity relationship combined with the crystallographic analysis of key compounds. We expect that our results will serve as a starting point for the design of specific and potent inhibitors against each of the two VRKs based on a pyridine scaffold.</p> </div>

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Development of Pyridine-Based Inhibitors for the Human Vaccinia-Related Kinases 1 and 2

10.26434/chemrxiv.7791464 ◽

2019 ◽

Author(s):

Ricardo Serafim ◽

Fernando de Souza Gama ◽

Caio dos Reis ◽

Stanley Vasconcelos ◽

André Santiago ◽

...

Keyword(s):

Cell Division ◽

Protein Kinases ◽

Neurological Disorders ◽

Therapeutic Potential ◽

Binding Mode ◽

Crystallographic Analysis ◽

Activity Relationship ◽

Cellular Functions ◽

Structure Activity ◽

Starting Point

<div> <p>Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compounds displayed <i>K</i><sub>D</sub> values of 190 nM and 401 nM for VRK1 and VRK2, respectively. Differences in compound binding mode and substituent preferences between the two VRKs were identified by the series structure-activity relationship combined with the crystallographic analysis of key compounds. We expect that our results will serve as a starting point for the design of specific and potent inhibitors against each of the two VRKs based on a pyridine scaffold.</p> </div>

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Practical Picture Processing

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100051700 ◽

1974 ◽

Vol 32 ◽

pp. 338-339

Author(s):

T. A. Welton

Keyword(s):

Radiation Damage ◽

Coherence Length ◽

Spatial Information ◽

State Of The Art ◽

Coherent Radiation ◽

The State ◽

Energy Spread ◽

Electron Micrograph ◽

Picture Processing ◽

Molecular Skeleton

Various authors have emphasized the spatial information resident in an electron micrograph taken with adequately coherent radiation. In view of the completion of at least one such instrument, this opportunity is taken to summarize the state of the art of processing such micrographs. We use the usual symbols for the aberration coefficients, and supplement these with £ and 6 for the transverse coherence length and the fractional energy spread respectively. He also assume a weak, biologically interesting sample, with principal interest lying in the molecular skeleton remaining after obvious hydrogen loss and other radiation damage has occurred.

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