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Publications 2011

Development of a scalable chiral synthesis of MK-3281, an inhibitor of the hepatitis C virus NS5B polymerase

Development of a scalable chiral synthesis of MK-3281, an inhibitor of the hepatitis C virus NS5B polymeraseBy Colarusso, Stefania; Conte, Immacolata; Di Filippo, Marcello; Ercolani, Caterina; MacKay, Angela C.; Palumbi, Maria Cecilia; Ferreira, Maria del Rosario Rico; Stansfield, Ian; Zaramella, Simone; Narjes, Frank; et al
From Synlett (2011), (11), 1527-1532. Language: English, Database: CAPLUS, DOI:10.1055/s-0030-1260790

The development of a scalable chiral synthesis for the HCV NS5B inhibitor MK-3281 I is being reported. Several alternative routes were explored and are being described.

Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.

By Lo Surdo, Paola; Bottomley, Matthew J.; Calzetta, Alessandra; Settembre, Ethan C.; Cirillo, Agostino; Pandit, Shilpa; Ni, Yan G.; Hubbard, Brian; Sitlani, Ayesha; Carfi, Andrea
From EMBO Reports (2011), 12(12), 1300-1305. Language: English, Database: CAPLUS, DOI:10.1038/embor.2011.205

The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low-d. lipoprotein receptor (LDLR) levels and cardiovascular health. We have detd. the crystal structure of LDLR bound to PCSK9 at neutral pH. The structure shows LDLR in a new extended conformation. The PCSK9 C-terminal domain is solvent exposed, enabling cofactor binding, whereas the catalytic domain and prodomain interact with LDLR epidermal growth factor(A) and β-propeller domains, resp. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling.

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Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1.

By Di Giovine, Paolo; Settembre, Ethan C.; Bhargava, Arjun K.; Luftig, Micah A.; Lou, Huan; Cohen, Gary H.; Eisenberg, Roselyn J.; Krummenacher, Claude; Carfi, Andrea
From PLoS Pathogens (2011), 7(9), e1002277. Language: English, Database: CAPLUS, DOI:10.1371/journal.ppat.1002277

Binding of herpes simplex virus (HSV) glycoprotein D (gD) to a cell surface receptor is required to trigger membrane fusion during entry into host cells. Nectin-1 is a cell adhesion mol. and the main HSV receptor in neurons and epithelial cells. The authors report the structure of gD bound to nectin-1 detd. by x-ray crystallog. to 4.0 Å resoln. The structure reveals that the nectin-1 binding site on gD differs from the binding site of the HVEM receptor. A surface on the first Ig-domain of nectin-1, which mediates homophilic interactions of Ig-like cell adhesion mols., buries an area composed by residues from both the gD N- and C-terminal extensions. Phenylalanine 129, at the tip of the loop connecting β-strands F and G of nectin-1, protrudes into a groove on gD, which is otherwise occupied by C-terminal residues in the unliganded gD and by N-terminal residues in the gD/HVEM complex. Notably, mutation of Phe129 to alanine prevents nectin-1 binding to gD and HSV entry. Together these data are consistent with previous studies showing that gD disrupts the normal nectin-1 homophilic interactions. Furthermore, the structure of the complex supports a model in which gD-receptor binding triggers HSV entry through receptor-mediated displacement of the gD C-terminal region.

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Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors.

By Ontoria, Jesus M.; Bufi, Laura Llauger; Torrisi, Caterina; Bresciani, Alberto; Giomini, Claudia; Rowley, Michael; Serafini, Sergio; Bin, Hu; Hao, Wu; Steinkuehler, Christian; et al
From Bioorganic & Medicinal Chemistry Letters (2011), 21(18), 5274-5282. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2011.07.031

The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a no. of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compds. displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compds. are valuable tools with which to probe the biol. of the Hh-pathway.

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N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists.

By Muraglia, Ester; Ontoria, Jesus M.; Branca, Danila; Dessole, Gabriella; Bresciani, Alberto; Fonsi, Massimiliano; Giuliano, Claudio; Llauger Bufi, Laura; Monteagudo, Edith; Palumbi, Maria Cecilia; et al
From Bioorganic & Medicinal Chemistry Letters (2011), 21(18), 5283-5288. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2011.07.030

Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compds. in in vivo studies.

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Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimid azo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, part 1.

By Malancona, Savina; Altamura, Sergio; Filocamo, Gessica; Kinzel, Olaf; Hernando, Jose Ignacio Martin; Rowley, Michael; Scarpelli, Rita; Steinkuehler, Christian; Jones, Philip
From Bioorganic & Medicinal Chemistry Letters (2011), 21(15), 4422-4428. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2011.06.024

The Hedgehog (Hh-) signaling pathway is a key developmental pathway which controls patterning, growth and cell migration in most tissues, but evidence has accumulated showing that many human tumors aberrantly reactivate this pathway. Smoothened antagonists offer opportunities for the treatment of malignancies dependent on the Hh pathway, and the most advanced clin. candidates are demonstrating encourage initial results. A novel series of [6,5]-bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione smoothened antagonists has been identified, and the series has been extensively explored to ascertain the key detriments for activity, demonstrating that the trans-2-phenylcyclopropyl and hydantoin ring systems are crit. for potency, while a variety of urea substituents can be tolerated. The combination of these optimal groups gives smoothened antagonists with activity in the low nanomolar range.

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Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclo- propyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydro-imidazo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, part 2.

By Kinzel, Olaf; Alfieri, Anna; Altamura, Sergio; Brunetti, Mirko; Bufali, Simone; Colaceci, Fabrizio; Ferrigno, Federica; Filocamo, Gessica; Fonsi, Massimiliano; Gallinari, Paola; et al
From Bioorganic & Medicinal Chemistry Letters (2011), 21(15), 4429-4435. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2011.06.023

The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compds. demonstrating encouraging results in initial clin. trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivs. with clean off-target profiles and good pharmacokinetic properties in preclin. species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 which was selected for further development.

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Intratumor RNA interference of cell cycle genes slows down tumor progression.

By Dharmapuri, S.; Peruzzi, D.; Marra, E.; Palombo, F.; Bett, A. J.; Bartz, S. R.; Yong, M.; Ciliberto, G.; La Monica, N.; Buser, C. A.; et al
From Gene Therapy (2011), 18(7), 727-733. Language: English, Database: CAPLUS, DOI:10.1038/gt.2011.27

Small interfering RNAs (siRNAs) are emerging as promising therapeutic tools. However, the widespread clin. application of such mols. as modulators of gene expression is still dependent on several aspects that limit their bioavailability. One of the most promising strategies to overcome the barriers faced by gene silencing mols. involves the use of lipid-based nanoparticles (LNPs) and viral vectors, such as adenoviruses (Ads). The primary obstacle for translating gene silencing technol. from an effective research tool into a feasible therapeutic strategy remains its efficient delivery to the targeted cell type in vivo. In this study, we tested the capability of LNPs and Ad to transduce and treat locally tumors in vivo. Efficient knockdown of a surrogate reporter (luciferase) and therapeutic target genes such as the kinesin spindle protein (KIF11) and polo-like kinase 1 were obsd. Most importantly, this activity led to a cell cycle block as a consequence and slowed down tumor progression in tumor-bearing animals. Our data indicate that it is possible to achieve tumor transduction with si/short hairpin RNAs and further improve the delivery strategy that likely in the future will lead to the ideal non-viral particle for targeted cancer gene silencing.

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