The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification

Abstract

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

“…Among these latter ones, neurodegeneration has a dramatic impact on the aging population. Protein kinases (PKs) represent very attractive and challenging drug targets for industry and academia to tackle complex disorders affecting peripheral and central tissues [1,2]. However, the development of PK-targeted therapies in neuroscience has not been primarily investigated due to several issues, including the multifactorial nature of the central nervous system (CNS) diseases, the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug by the U.S. Food and Drug Administration (FDA) [3,4].…”

“…Ghose et al, analyzing the physicochemical property and the chemical structural profiles of several CNS and non-CNS oral drugs in a comparative fashion, provided guidelines for designing high-quality CNS drugs. According to their property distribution study and the classification tree, a compound with an ideal property profile should possess a topological molecular polar surface area of <76 Å 2 (25-60 Å 2 ), at least one nitrogen (including one aliphatic amine), fewer than seven (two to four) linear chains outside of rings, less than three (preferred zero or one) polar hydrogen atoms, the volume of 740-970 Å 3 , the solvent accessible surface area of 460-580 Å 2 , and a positive QikProp (QP) CNS parameter (https://www.schrodinger.com/products/qikprop, accessed on 26 July 2021) [9]. An additional approach toward assessment of drug-likeness properties affecting overall brain permeability and very useful in prioritizing lead candidates consists in the Pfizer's CNS multiparameter optimization [10], which takes into account calculated partition coefficient (ClogP), calculated distribution coefficient at pH 7.4 (ClogD), molecular weight (M W ), acid dissociation constant (pK a ) of ionizable groups, together with total polar surface area and the number of hydrogen bond donors.…”

“…The rediscovery of "old molecules" fits with the need for poorly addressed therapeutic areas in which the CNS-related pathologies represent a leading field [11,12]. Great examples in this scenario are saracatinib (1) and masitinib (2), which are two well-known inhibitors of FYN kinase firstly developed as anti-cancer agents. Compound 1 (Figure 1), also known as AZD0530, is a highly selective Src family kinases (SFKs) inhibitor developed by AstraZeneca in 2006 [13].…”

“…Figure 1. Chemical structures of saracatinib (1) and masitinib (2), two FYN inhibitors firstly developed for the treatment of cancer and repurposed as CNS-agents.…”

AD Informer Set: Chemical tools to facilitate Alzheimer’s disease drug discovery

“…These sets, while not comprised of chemical probes, have been shared with over 300 laboratories and have resulted in many new research findings, grants, and publications [18]. Furthermore, experience with these sets informed assembly of the kinase chemogenomic set (KCGS), which only includes kinase inhibitors for nearly half of the human kinome that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays [19]. Like PKIS/PKIS2, KCGS is made available with all associated annotation to all interested investigators.…”