The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

No abstract

Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.

Dimethyl (1S,2S,4S,5S)‐4‐allyloxy‐5‐(α‐mannosyloxy)cyclohexane‐1,2‐dicarboxylate (3) was designed as a structural mimic of α(1,2)mannobioside (1). Its synthesis and structural analysis by NMR spectroscopy and molecular modelling are described. The results show that 3, like 1, populates two low‐energy conformations — stacked (S) and extended (E) — that are in fast dynamic equilibrium around the glycosidic linkage. Thus, the data confirm the expectation that the pseudo‐disaccharide can be used as a structural mimic of mannobioside. The mannosidase stability of 3 was found to be significantly higher (sixfold) than that of natural mannobioside. This is a very useful feature of this mimic and is encouraging for its future development. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

No abstract

More patient-compliant orally available PARP-1 inhibitor clinical candidates, along with their possible use as single agents in specific, molecularly defined cancer indications, increase the expectations for this therapeutic approach. The growing understanding of the biological role of other PARPs, such as Tankyrase 1, may be of interest as new potential targets. Besides the classical NAD-mimicking pharmacophore, additional compounds, which either do not resemble nicotinamide or exploit different binding sites, are emerging.

Carbohydrates Carbohydrates U 0500 Mimics of Ganglioside GM1 as Cholera Toxin Ligands: Replacement of the GalNAc Residue. -(BERNARDI*, A.; AROSIO, D.; MANZONI, L.; MONTI, D.; POSTERI, H.; POTENZA, D.; MARI, S.; JIMENEZ-BARBERO, J.; Org. Biomol. Chem 1 (2003) 5, 785-792; Dip. Chim. Org. Ind., Univ. Stud. Milano, CNR, I-20133 Milano, Italy; Eng.) -S. Adam 26-213

[chemical reaction: see text]. The synthesis of the C11H5 marine sponge alkaloids, (Z)-hymenialdisine and (Z)-2-debromohymenialdisine, is described. A key step was the condensation between aldisine or its monobromo derivative and a new, efficient imidazolinone-based glycociamidine precursor. In the first case, the main product turned out to be the unprecedented (+/-)-endo-2-debromohymenialdisine.