Somatic point mutations
at a key arginine residue (R132) within
the active site of the metabolic enzyme isocitrate dehydrogenase 1
(IDH1) confer a novel gain of function in cancer cells, resulting
in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite.
Elevated 2-HG levels are implicated in epigenetic alterations and
impaired cellular differentiation. IDH1 mutations have been described
in an array of hematologic malignancies and solid tumors. Here, we
report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1
mutant enzyme that exhibits profound 2-HG lowering in tumor models
and the ability to effect differentiation of primary patient AML samples
ex vivo. Preliminary data from phase 1 clinical trials enrolling patients
with cancers harboring an IDH1 mutation indicate that AG-120 has an
acceptable safety profile and clinical activity.
Inhibitors of mutant
isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated
enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate
(2-HG) and are under clinical investigation for the treatment of several
cancers harboring an IDH mutation. Herein, we describe the discovery
of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor
of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to
characterize the compound binding site, leading to an understanding
of the dual mutant inhibition. Furthermore, vorasidenib penetrates
the brain of several preclinical species and inhibits 2-HG production
in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib
represents a novel dual mIDH1/2 inhibitor and is currently in clinical
development for the treatment of low-grade mIDH glioma.
Ribonucleotide reductase inhibitors enhance the anti-HIV-1 activities of a variety of nucleoside analogs, including those that act as chain terminators and those that increase the HIV-1 mutation rate. However the use of these ribonucleotide reductase inhibitors is limited by their associated toxicities. The hydroxylated phytostilbene resveratrol has activity in a host of systems including inhibition of ribonucleotide reductase and has minimal toxicity. Here we synthesized derivatives of resveratrol and examined them for anti-HIV-1 activity and their ability to enhance the antiviral activity of decitabine, a nucleoside analog that decreases viral replication by increasing the HIV-1 mutation rate. The data demonstrates six of the derivatives have anti-HIV-1 activity greater than resveratrol. However, only resveratrol acted in synergy with decitabine to inhibit HIV-1 infectivity. These results reveal novel resveratrol derivatives with anti-HIV-1 activity that may have mechanisms of action that differ from the drugs currently used to treat HIV-1.
Oligonucleotides that contain up to three aminopropyl nucleoside analogues have been synthesized. Dimers of aminopropyl adenine and thymidine were prepared and used as building blocks by applying phosphoramidite chemistry. Both R and S isomers of the aminopropyl nucleosides were used. This incorporation led to a reduction of thermal stability of double-stranded DNA. Furthermore, the (R)-adenine analogue, which yielded (S)-APNA, can be considered as a candidate for universal base pairing.
The synthesis and antiviral evaluation of new acyclic phosphonate nucleosides related to HPMPC (Cidofovir) has been described. These aminopropyl phosphonate nucleosides 1-3 have an amino function within either the acyclic chain (series 2 and 3) or as substituent (series 1). Both purine and pyrimidine nucleotide analogues have been synthesized. In contrast to HPMPC the oxygen analogue of 2c, only a weak antiherpes virus activity could be demonstrated for 2b and 2c.
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