Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
Mutant isocitrate dehydrogenase-1 and -2 (mIDH-1 and mIDH-2) can lead to cancer by producing the oncometabolite d-2-hydroxyglutarate. Many types of glioma and acute myeloid leukemia harbor mutations in both IDH-1 and IDH-2, but current inhibitors are selective for only one of the isoforms. In this issue’s Featured Letter (DOI: 10.1021/acsmedchemlett.9b00509, Konteatis et al. report the preclinical characterization of vorasidenib (AG-881), a dual inhibitor of mIDH-1 and mIDH-2.
Vorasidenib demonstrates low nanomolar inhibition of wild-type and mutant IDH-1 and IDH-2 and possesses good brain-to-plasma ratios. X-ray crystal structures of vorasidenib bound to both mIDH-1 and -2 elucidate the allosteric binding site, which sits at the interface of two monomers. The authors demonstrate that d-2-hydroxyglutarate levels are substantially decreased in an orthotopic xenograft model of glioma. Vorasidenib is currently in clinical trials in patients with solid tumors.
Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors
SET and MYND Domain Containing Protein 3 (SMYD3) is a lysine methyltransferase that methylates lysine 5 of Histone H4 (H4K5) and lysine 260 of mitogen-activated protein kinase kinase 2 (MEKK2). There is strong evidence that SMYD3 inhibition may be a viable therapeutic strategy in several types of cancer.
In this issue, Su et al. (DOI: 10.1021/acsmedchemlett.9b00493) describe a series of isoxazole amides that inhibit the activity of SMYD3. This well-developed structure–activity relationship was enabled by four X-ray cocrystal structures, which are reported in this issue for the first time. Aided by these insights, the authors optimized a high-throughput screening hit (1) into a high-affinity lead (49) that is active in vitro and in vivo. Compound 49 shows good pharmacokinetic properties and is a promising tool compound for SMYD3 inhibition studies.
Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases
RORγt is a transcription factor and member of the nuclear receptor superfamily that regulates the differentiation and development of T helper 17 (Th17) cells. Stimulated Th17 cells regulate a number of cytokines, including IL-17s, which have been clinically validated as drug targets in autoimmune diseases by anti-IL-17 monoclonal antibodies. Inhibiting RORγt activity may provide an alternative approach for treating autoimmune disorders.
Some of the previously described RORγt inhibitors, including MRL-871, suffered from poor activity and pharmacokinetic properties. In this issue, Zhang et al. (DOI: 10.1021/acsmedchemlett.9b00431) describe a potent lead molecule (25) that binds to an allosteric site on RORγt and inhibits its activity. Key features of the structure–activity relationship include inclusion of a fluoro-substituent at the 4-position of the indazole core, which enhanced cellular activity, and replacement of a benzoic acid with a piperidine β-hydroxycarboxylic acid to enhance biochemical and cellular activities. Additionally, compound 25 has enhanced physicochemical and pharmacokinetic properties, and it shows inhibition in an animal model of RORγt activity. An X-ray cocrystal structure shows compound 25 bound to an allosteric site on the ligand-binding domain of RORγt. Taken together, the results from this report describe a good chemical probe for interrogating RORγt activity.
