5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.

Several novel, fully synthetic, carbohydrate-based antitumor vaccines have been assembled. Each construct consists of multiple cancer-related antigens displayed on a single polypeptide backbone. Recent advances in synthetic methodology have allowed for the incorporation of a complex oligosaccharide terminating in a sialic acid residue (i.e., GM2) as one of the carbohydrate antigens. Details of the vaccine synthesis as well as the results of preliminary immunological investigations are described herein.

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg. Having identified an allosteric, induced pocket of IDH1, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate (), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. () has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.

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ObjectiveTo replace camera-based three-dimensional motion analyzers which are widely used to analyze body movements and gait but are also costly and require a large dedicated space, this study evaluates the validity and reliability of inertial measurement unit (IMU)-based systems by analyzing their spatio-temporal and kinematic measurement parameters.MethodsThe investigation was conducted in three separate hospitals with three healthy participants. IMUs were attached to the abdomen as well as the thigh, shank, and foot of both legs of each participant. Each participant then completed a 10-m gait course 10 times. During each gait cycle, the hips, knees, and ankle joints were observed from the sagittal, frontal, and transverse planes. The experiments were conducted with both a camerabased system and an IMU-based system. The measured gait analysis data were evaluated for validity and reliability using root mean square error (RMSE) and intraclass correlation coefficient (ICC) analyses.ResultsThe differences between the RMSE values of the two systems determined through kinematic parameters ranged from a minimum of 1.83 to a maximum of 3.98 with a tolerance close to 1%. The results of this study also confirmed the reliability of the IMU-based system, and all of the variables showed a statistically high ICC.ConclusionThese results confirmed that IMU-based systems can reliably replace camera-based systems for clinical body motion and gait analyses.

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High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)-pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1 R132H . Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1 wt . Initial structure−activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood−brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model. KEYWORDS: Mutant IDH1 inhibitor, allosteric inhibition, 2-HG, preclinical in vivo activity, 3-pyrimidin-4-yloxazolidin-2-one, chirality-defined potency H otspot heterozygous mutations in human cytoplasmic isocitrate dehydrogenase 1 (IDH1) at Arg 132 (R132*) have been identified in multiple cancer types, including acute myeloid leukemia (AML), glioma, chondrosarcoma, and cholangiocarcinoma. 1 These mutations have been shown to confer a neomorphic catalytic activity to produce high levels of intracellular R-2-hydroxyglutarate (2-HG) and effect downstream epigenetic markers on DNA and proteins. Recent clinical trials in AML patients with a specific inhibitor of IDH1 has shown clinical benefit, confirming the causal link between this genetic mutation, the production of 2-HG, and cancer.11 Efforts herein focused on the identification of compounds that could potentially target all classes of mutant-IDH1 tumors, including those in the brain.The substrate-binding site of mutant IDH1 is highly polar as defined by the amino acids lining the pocket (Figure 1), in addition to the active-site magnesium ion and NADPH cofactor. This suggests a low probability of being able to optimize a compound for potent binding to this site while also fulfilling the criteria most conducive to crossing the blood− brain barrier (BBB).12 It was decided to explore the identification of catalytic inhibitors with different mechanisms of action, which may bind distal to this polar substrate-binding site.High throughput screening was carried out with a NADPH fluorescence-based biochemical assay using IDH1 R132H homodimer protein, and orthogonal biochemical inhibition confirmation using an LCMS readout of 2-HG levels. Compounds 1a and 1b were identified as selective and functional inhibitors of IDH1R132H from this screen. Both 1a and 1b were screened as diastereomeric mixtures at the amine (Table 1, Am), which necessitated the independent synthesis of the four separate stereoisomers in order to determine the chiral preference for ligand binding. Potency was found to be most strongly dependent upon the chirality at the amine center (Am), . Amino acids lining the pocket are highl...