Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III

Shen, Yongchun; Boivin, Roch P.; Yoneda, Naoto; Du, Hong; Schiller, Shawn; Matsushima, Tomohiro; Goto, Masaki; Shirota, Hiroshi; Gusovsky, Fabián; Lemelin, Charles; Jiang, Yimin; Zhang, Zhiyi; Pelletier, Robert; Ikemori-Kawada, Megumi; Kawakami, Yoshiyuki; Inoue, Atsushi; Schnaderbeck, Matthew J.; Wang, Yuan

doi:10.1016/j.bmcl.2010.03.087

Cited by 34 publications

(24 citation statements)

References 7 publications

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“…Indeed, some of the identified kinase inhibitors that rescue ⌬F508-CFTR are already in clinical trials for the treatment of other diseases. For example, E6201, a (5Z)-7-Oxozeaenol derivative, is now in clinical trials for the treatment of cancer (phase I (ClinicalTrials.gov identifier: NCT00794781)) and Psoriasis (phase II (ClinicalTrials.gov identifiers: NCT01268527, NCT00539929)) (27,28). SU6668 (Orantinib) is currently in clinical trials for advanced solid tumors (phase I completed (ClinicalTrials.gov identifier: NCT00024206)) and AZD0530 (Saracatinib) is in phase II clinical trials for prostate, pancreatic, breast, colorectal, bone, and ovarian cancers (ClinicalTrials.gov identifiers: NCT01267266, NCT00735917, NCT00558272, NCT00397878, NCT00610714).…”

Section: Discussionmentioning

confidence: 99%

Use of Kinase Inhibitors to Correct ΔF508-CFTR Function

Trzcińska-Daneluti

Nguyen

Jiang

et al. 2012

Molecular & Cellular Proteomics

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Section: Discussionmentioning

confidence: 99%

Use of Kinase Inhibitors to Correct ΔF508-CFTR Function

Trzcińska-Daneluti

Nguyen

Jiang

et al. 2012

Molecular & Cellular Proteomics

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“…They observed that the cis‐enone reacts with glutathione and that the reaction is accelerated in the presence of glutathione transferase. Two compounds were subsequently synthesized, ER‐803064, 8 , and E‐6201, 9 …”

Section: Kinase Selectivity and Sarmentioning

confidence: 99%

(5Z)‐7‐Oxozeaenol: A novel and potent resorcylic acid lactone kinase inhibitor with a cis‐enone Michael acceptor

Ellestad

2018

Chirality

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In this review, evidence is presented from a number of research groups over the past two decades that show that (5Z)‐7‐oxozeaenol, an initially biologically uninteresting fungal metabolite, is a remarkably selective and potent kinase inhibitor with important antiproliferative and anti‐inflammatory properties. Taken together, this research shows (5Z)‐7‐oxozeaenol to be a surprisingly selective and competitive ATP binder in which the aromatic ring of the resorcylic lactone mimics the adenine ring of ATP; that it binds covalently to a conserved cysteine at a metabolically unstable cis‐enone Michael acceptor; the conformational importance of the macrocycle, which depends on the absolute stereochemistry and hydrogen bonding properties of the 8,9‐diol; and the success of medicinal chemistry in stabilizing the cis‐enone.

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“…Based on previous study studies that C14 position can tolerate substitutions, Shen et al designed analog 82 Fig. [47] Both compounds had good oral bioavailability and were tested on inflammatory animal models. Compound 82 showed very good potency (IC 50 : 23 nM) and impressive oral bioavailability in mouse (49%).…”

Section: -3mentioning

confidence: 99%

Cis-enone Resorcylic Acid Lactones (RALs) as Irreversible Protein Kinase Inhibitors

Wei¹,

Jian-hua²,

Li³

et al. 2012

CPD

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Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cis-enone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders.

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Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III

Cited by 34 publications

References 7 publications

Use of Kinase Inhibitors to Correct ΔF508-CFTR Function

Use of Kinase Inhibitors to Correct ΔF508-CFTR Function

(5Z)‐7‐Oxozeaenol: A novel and potent resorcylic acid lactone kinase inhibitor with a cis‐enone Michael acceptor

Cis-enone Resorcylic Acid Lactones (RALs) as Irreversible Protein Kinase Inhibitors

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