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The specific mycobacterial methyl polysaccharides 3- O -methyl mannose polysaccharide (MMP) and the 6- O -methyl glucose lipopolysaccharides (MGLPs) were shown to modulate the fatty acid biosynthesis by the mycobacterial fatty acid synthetase I (FAS I). This activity is attributed to their fatty acid complexing properties allowing the release of the neo synthesized fatty acyl chain from the enzyme and probably their transport in the cell. To elucidate, at a molecular level, the mechanism of this unusual kind of polysaccharide-lipid biological interaction, we first analyzed, by mass spectrometry and proton nuclear magnetic resonance (1H NMR) spectroscopy, the structure of the polysaccharidic backbone (MGPs) of the MGLPs from Mycobacterium bovis BCG. This work reveals that this strain produces a new kind of MGP containing an unusual monosaccharide never described in the mycobacterial genus: a 2- N -acetyl-2,6-dideoxy-beta-glucopyranosyl. In addition,1H NMR data afforded evidence for the revision of three glycosidic linkages described previously. These modifications affect mainly the reducing end tetrasaccharide and have great consequences on the previously proposed molecular model of the MGP.

BackgroundThis phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics and pharmacodynamics of combination therapy with the HDM2 inhibitor SAR405838 and the MEK1/2 inhibitor pimasertib administered orally once daily (QD) or twice daily (BID) in locally advanced or metastatic solid tumours (NCT01985191).MethodsPatients with locally advanced or metastatic solid tumours with documented wild-type TP53 and RAS or RAF mutations were enroled. A 3 + 3 dose-escalation design was employed. The primary objective was to assess maximum tolerated dose (MTD).ResultsTwenty-six patients were treated with SAR405838 200 or 300 mg QD plus pimasertib 60 mg QD or 45 mg BID. The MTD was SAR405838 200 mg QD plus pimasertib 45 mg BID. The most common dose-limiting toxicity was thrombocytopenia. The most frequently occurring treatment-related adverse events were diarrhoea (81%), increased blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). No significant drug–drug interactions were observed. The biomarkers MIC-1 and pERK were, respectively, upregulated and downregulated in response to study treatment. In 24 efficacy-evaluable patients, one patient (4%) had a partial response and 63% had stable disease.ConclusionsThe safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed.

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