Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screening

The mediator complex-associated cyclin dependent kinase CDK8 regulates beta-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies

2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1SER727 phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing

Synthèse de dérivés de l'acide tétronique et de l'acide pulvinique. Synthèse totale de la norbadione A.

Many pigments of fungi, such as norbadione A and pulvinic acid derivatives, revealed remarkable antioxidant activity. In this thesis, we were interested in the synthesis of these compounds, which could be used as agents for protection against ionizing radiations. In this context, a new synthetic pathway to tetronic acid derivatives has been developed from methyl arylacetates and hydroxyesters. The methodology allowed one-step synthesis of several 3-aryltetronic acids and related heterocyclic compounds. From one tetronic acid derivative, three natural pulvinic acid esters have been prepared, by a very direct way and with very good yields. In the total synthesis of norbadione A, two pathways have been studied. The first one relied on the methodology developed in this thesis for the synthesis of pulvinic acids. The preparation of an advanced intermediate was obtained. The second pathway, in which the key step was a double Suzuki-Miyaura cross-coupling, led to the first total synthesis of norbadione A.Plusieurs pigments de champignons, tels que la norbadione A et des dérivés de l'acide pulvinique, ont révélé une activité antioxydante remarquable. Au cours de cette thèse, nous nous sommes intéressés à la synthèse de ces composés qui pourraient être employés comme agents de protection contre les rayonnements ionisants. Dans ce contexte, une nouvelle voie d'accès à des dérivés de l'acide tétronique a été mise au point à partir d'arylacétates de méthyle et d'hydroxyesters. La méthodologie développée a permis, en une seule étape, la synthèse de plusieurs acides 3-aryltétroniques et de composés hétérocycliques apparentés. A partir d'un dérivé de l'acide tétronique, trois esters d'acides pulviniques naturels ont été préparés par une voie très directe et avec de bons rendements. Dans le cadre de la synthèse totale de la norbadione A, deux voies de synthèse ont été étudiées. La première consiste à appliquer la méthodologie développée au cours de cette thèse pour la synthèse d'acides pulviniques. Les travaux réalisés ont ainsi permis la synthèse d'un intermédiaire avancé. La seconde voie, dont l'étape clé est un double couplage de Suzuki-Miyaura, a conduit à la première synthèse totale de la norbadione A

Synthèse de dérivés de l'acide tétronique et de l'acide pulvinique

Plusieurs pigments de champignons, tels que la norbadione A et des dérivés de l'acide pulvinique, ont révélé une activité antioxydante remarquable. Au cours de cette thèse, nous nous sommes intéressés à la synthèse de ces composés qui pourraient être employés comme agents de protection contre les rayonnements ionisants. Dans ce contexte, une nouvelle voie d'accès à des dérivés de l'acide tétronique a été mise au point à partir d'arylacétates de méthyle et d'hydroxyesters. La méthodologie développée a permis, en une seule étape, la synthèse de plusieurs acides 3-aryltétroniques et de composés hétérocycliques apparentés. A partir d'un dérivé de l'acide tétronique, trois esters d acides pulviniques naturels ont été préparés par une voie très directe et avec de bons rendements.Dans le cadre de la synthèse totale de la norbadione A, deux voies de synthèse ont été étudiées. La première consiste à appliquer la méthodologie développée au cours de cette thèse pour la synthèse d acides pulviniques. Les travaux réalisés ont ainsi permis la synthèse d'un intermédiaire avancé. La seconde voie, dont l étape clé est un double couplage de Suzuki-Miyaura, a conduit à la première synthèse totale de la norbadione A.Several mushrooms pigments, such as norbadione A and pulvinic acid derivatives, exhibit a remarkable antioxidant activity. In the course of this PhD thesis, we have been interested in the synthesis of these compounds, which could be used as protection agents against ionizing radiations. In this context, a novel access to tetronic acid derivatives has been developed from methyl arylacetates and hydroxyesters. The methodology allows the synthesis of several 3-aryltetronic acids and related heterocyclic compounds in one step. From one of these tetronic acid derivatives, three natural esters of pulvinic acids have been prepared straightforwardly and in good yields. With regards to norbadione A total synthesis, two routes have been envisioned. The first one consists in the application of the methodology developed for the synthesis of pulvinic acids. This work has allowed us to synthesise a key bis(tetronic) intermediate. The second route, for which the key step is a double Suzuki-Miyaura cross-coupling, has allowed to complete the first total synthesis of norbadione A.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Evaluation of polymer-supported vinyltin reagents in the Stille cross-coupling reaction

International audienc

Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor

International audienceBreast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC