Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor–like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100–1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors

Etude par modélisation moléculaire d'un polymère à usage thérapeutique (le poly(méthylidène malonate 2.1.2), structure tridimensionnelle, propriétés moléculaires et influence de la solvatation)

ORLEANS-BU Sciences (452342104) / SudocSudocFranceF

Identification and characterization of a phenyl-thiazolyl-benzoic acid derivative as a novel RAR/RXR agonist

Objective To identify an agonist of RXRα and RARα with reduced undesired profiles of all-trans retinoic acid for differentiation-inducing therapy of acute promyelocytic leukemia (APL), such as its susceptibility to P450 enzyme, induction of P450 enzyme, increased sequestration by cellular retinoic acid binding protein and increased expression of P-glycoprotein, a virtual screening was performed. Results and conclusion In this study, a phenyl-thiazolyl-benzoic acid derivative (PTB) was identified as a potent agonist of RXRα and RARα. PTB was characterized in nuclear receptor binding, reporter gene, cell differentiation and cell growth assays. PTB bound directly to RXRα and RARα, but not to PPARα, δ(β) or γ. PTB fully activated reporter genes with enhancer elements for RXRα/RXRα, and partially activated reporter genes with enhancer elements for RARα/RXRα, PPARδ(β) and PPARγ. Furthermore, PTB induced differentiation and inhibited the growth of human APL cells. Thus, PTB is a novel dual agonist of RXRα and RARα and works as both a differentiation inducer and a proliferation inhibitor to leukemic cells

Novel Concept for Super-Soft Topical Drugs: Deactivation by an Enzyme-Induced Switch into an Inactive Conformation

We present a novel concept for the design of soft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor 2 releases hydroxypyridine 3. Due to hydroxypyridine-pyridone tautomerism, 3 undergoes a rapid conformational change preventing the compound to assume the bioactive conformation required for binding to JAK kinases. We demonstrate that the hydrolysis in human blood and the subsequent shape change lead to the deactivation of 2

Identification of a potent Jak3 inhibitor with high selectivity within the Jak kinase family

We describe a synthetic approach towards the rapid modification of phenyl-indolyl maleimides and the discovery of the highly potent Jak3 inhibitor 1 with high selectivity within the Jak kinase family. We provide a rational for this unprecedented selectivity based on the X-ray crystal structure of an analog of 1 bound to the ATP-binding site of Jak3. While equally potent compared to the Pfizer pan Jak inhibitor CP-690,550 in an enzymatic Jak3 assay compound 1 was found to be substantially less potent in cellular assays measuring cytokine-triggered signaling through cytokine receptors containing the common gamma chain (C). Contrary to compound 1, CP-690,550 inhibited Jak1 in addition to Jak3. Similar cell-associated amounts of compound 1 and CP-690,550 were determined. As Jak3 always cooperates with Jak1 for signaling we speculate that the specific inhibition of Jak3 is insufficient to block C cytokine signal transduction required for strong immunosuppression

New scoring functions for virtual screening from molecular dynamics simulations with a quantum-refined force-field (QRFF-MD). Application to cyclin-dependent kinase 2.

A recently introduced new methodology based on ultrashort (50-100 ps) molecular dynamics simulations with a quantum-refined force-field (QRFF-MD) is here evaluated in its ability both to predict protein-ligand binding affinities and to discriminate active compounds from inactive ones. Physically based scoring functions are derived from this approach, and their performance is compared to that of several standard knowledge-based scoring functions. About 40 inhibitors of cyclin-dependent kinase 2 (CDK2) representing a broad chemical diversity were considered. The QRFF-MD method achieves a correlation coefficient, R(2), of 0.55, which is significantly better than that obtained by a number of traditional approaches in virtual screening but only slightly better than that obtained by consensus scoring (R(2) = 0.50). Compounds from the Available Chemical Directory, along with the known active compounds, were docked into the ATP binding site of CDK2 using the program Glide, and the 650 ligands from the top scored poses were considered for a QRFF-MD analysis. Combined with structural information extracted from the simulations, the QRFF-MD methodology results in similar enrichment of known actives compared to consensus scoring. Moreover, a new scoring function is introduced that combines a QRFF-MD based scoring function with consensus scoring, which results in substantial improvement on the enrichment profile

An orally bioavailable Syk inhibitor with activity in a rat PK/PD model

Design and optimization of benzo and pyridothiazoles and isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. But in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued

Design of a Super-Soft Topical JAK Inhibitor, which Is Efficacious in Human Skin but Rapidly Deactivated in Blood

We describe the discovery and characterization of the super-soft topical JAK inhibitor 3(R), which is potent in biochemical and cellular assays as well as in human skin models. In blood, the neutral ester 3(R) is rapidly hydrolyzed (t1/2~6 min) to the corresponding charged carboxylic acid 4 exhibiting >30-fold reduced permeability. Consequently, acid 4 does not reach the intracellular JAK kinases and is inactive in cellular assays and in blood. Thus, hydrolysis by blood esterases leads to the rapid deactivation of the topically active ester 3(R) at a rate beyond the maximal hepatic clearance

Indolyl-naphthyl-maleimides as potent and selective Inhibitors of Protein Kinase C-alpha/beta

The indolyl-naphthyl maleimide 7 is a potent inhibitor of the classical PKC isotypes PKC-alpha/beta and shows excellent selectivity over the novel PKC isotypes delta, epsilon, eta and theta and other kinases belonging to the AGC family. The SAR around 7 as well as the physico-chemical characteristics of selected derivatives and their activity in T and B cell activation and proliferation assays are discussed

Molecular Informatics as an Enabling in silico Technology Platform for Drug Discovery

The molecular informatics platform, as implemented today in the Molecular and Library Informatics (MLI) Technology Program at Novartis Institutes for BioMedical Research (NIBR) Discovery Technologies, will be presented. The mission of the MLI program is primarily defined to contribute to the selection of screening hit and lead compounds using in silico methods. The MLI technology program aims to provide an integrated pipeline of computational methods for high-throughput in silico screening combining specific cheminformatics, bioinformatics, docking and 3D pharmacophore applications. The four core activities of the group include: 1) Molecular diversity management; 2) In silico screening using HTD (high-throughput docking) and 3D pharmacophore searching; 3) Integrated analysis of HTS (high-throughput screening) and profiling data; and 4) Database management and software engineering in the field of in silico screening. The contribution of these activities to the drug discovery process will be summarized together with novel trends in the field