ABSTRACT
A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor/chemistry , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Epoxy Compounds/chemical synthesis , Epoxy Compounds/metabolism , Macrolides/chemical synthesis , Macrolides/metabolism , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/chemistry , RNA Splicing/drug effects , Ribonucleoprotein, U2 Small Nuclear/antagonists & inhibitors , Ribonucleoprotein, U2 Small Nuclear/chemistry , Antineoplastic Agents/chemistry , Binding Sites , Epoxy Compounds/chemistry , Humans , Macrolides/chemistry , RNA Splicing FactorsABSTRACT
The RAS/RAF/MEK/ERK signaling pathway has been a major clinical focus in oncology research in recent years. A clearer association of B-RAF mutations to cancers such as melanoma, papillary thyroid cancer and others has brought an increasing interest in chemotherapeutics that target this cellular signaling pathway. In this review, the authors summarize the current understanding of science and therapeutic use of the MEK inhibitors targeting the RAS/RAF/ MEK/ERK pathway. Clinical progresses of PD0325901 and AZD6244 are highlighted in addition to developments of new MEK inhibitors. Recently disclosed MEK inhibitors in two sub-divided classes, ATP noncompetitive and ATP competitive inhibitors are discussed.
