JAK1,
JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family.
They play critical roles in cytokine signaling. Constitutive activation
of JAK/STAT pathways is associated with a wide variety of diseases.
Particularly, pSTAT3 is observed in response to the treatment with
inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and
AKT and is associated with resistance or poorer response to agents
targeting these pathways. Among the JAK family kinases, JAK1 has been
shown to be the primary driver of STAT3 phosphorylation and signaling;
therefore, selective JAK1 inhibition can be a viable means to overcome
such treatment resistances. Herein, an account of the medicinal chemistry
optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective
JAK1 kinase inhibitor, is reported. Compound 21 has good
preclinical pharmacokinetics. Compound 21 displayed an
enhanced antitumor activity in combination with an approved EGFR inhibitor,
osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft
NCI-H1975 model.
MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1.
Tumors have evolved a variety
of methods to reprogram conventional
metabolic pathways to favor their own nutritional needs, including
glutaminolysis, the first step of which is the hydrolysis of glutamine
to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor
could potentially target certain cancers by blocking the tumor cell’s
ability to produce glutamine-derived nutrients. Starting from the
known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl
sulfide, we describe the medicinal chemistry evolution of a series
from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic
properties to cell potent examples with reduced molecular weight and
lipophilicity, leading to compounds with greatly improved oral exposure
that demonstrate in vivo target engagement accompanied by activity
in relevant disease models.
ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.
The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor ‘example 172’ (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design.
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