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

Abstract

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.

Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors

“…To our knowledge, this represents the most cytotoxic MAP2K7 inhibitor toward T-ALL lines of interest with the exception of 1 and OTSSP167 . The cytotoxicity of these compounds is likely multifactorial given their promiscuity, , and for 1 , low MAP2K7 potency (IC 50 = 1.3 μM vs 80 nM for MAP2K1 and 80 nM for TAK1) . EGFR inhibitor erlotinib failed to induce cytotoxicity at similar concentrations, thereby suggesting that the effect on cell viability is likely driven by MAP2K7 inhibition (Figure SI-11).…”

Semisynthesis of Hypothemycin Analogues Targeting the C8–C9 Diol

“…The cis -enone moiety in RALs is well known to be crucial for their irreversible inhibition of TAK1; ,,− ,, however, limited information is available on the role of the C8–C9 diol in the TAK1 inhibition process, and it is not clear if these alcohol groups are essential for the activity of cis -enone RALs. If one or both of these alcohols are modified, they could serve as a functional handle to improve various physical properties of the molecule while also accessing new intellectual property, which is required for further development of natural product leads .…”