HPI 1

Hedgehog (Hh) signaling inhibitor. Inhibits Sonic hedgehog (Shh)-, SAG- and Gli-induced Hh pathway activation in Shh-LIGHT2 cells (IC50 values are 1.5, 1.5, 4 and 6 μM for Shh-, SAG-, Gli2- and Gli1-induced activation). Also inhibits Hh pathway activation

Effects of therapy using a helicase-primase inhibitor (HPI) in mice infected with deliberate mixtures of wild-type HSV-1 and an HPI-resistant UL5 mutant.[Pubmed:20420855]

Antiviral Res. 2010 Jul;87(1):67-73.

Point mutations in the HSV-1 UL5 (helicase) gene confer resistance to helicase-primase inhibitors (HPIs), e.g. BAY 57-1293. Such mutations normally occur at a frequency of < or =10(-6)PFU. However, individual HSV-1 laboratory strains and some clinical isolates contained resistance mutations (e.g. UL5: Lys356Asn) at 10(-4)PFU. To address the possibility that pre-existing mutants at high frequency might have an impact on therapy using HPIs, deliberate mixtures were prepared to contain the SC16 UL5: Lys356Asn mutant in SC16 wild-type in the proportion of 1/500 or 1/50PFU. Mice were infected in the neck-skin with 5x10(4)PFU/mouse of wt alone, mutant alone, or the respective mixture. The mutant could not be detected in infectious virus yields from mice inoculated with the 1/500 mixture. However, resistant mutant was recovered from some treated mice inoculated with the 1/50 mixture. All mice inoculated with mixtures remained responsive to BAY 57-1293-therapy with no increase in clinical signs compared to treatment of wt-infected mice.

Bis{2-[(phenylimino)ethyl]-1H-pyrrol-1-ido-kappa(2)N,N'}nickel(II): a supramolecular structure formed by C-Hpi hydrogen bonds.[Pubmed:23907874]

Acta Crystallogr C. 2013 Aug;69(Pt 8):851-4.

In the title compound, [Ni(C(1)(2)H(1)(1)N(2))(2)], the NiII cation lies on an inversion centre and has a square-planar coordination geometry. This transition metal complex is composed of two deprotonated N,N'-bidentate 2-[(phenylimino)ethyl]-1H-pyrrol-1-ide ligands around a central NiII cation, with the pyrrolide rings and imine groups lying trans to each other. The Ni-N bond lengths range from 1.894 (3) to 1.939 (2) A and the bite angle is 83.13 (11) degrees . The Ni-N(pyrrolide) bond is substantially shorter than the Ni-N(imino) bond. The planes of the phenyl rings make a dihedral angle of 78.79 (9) degrees with respect to the central NiN(4) plane. The molecules are linked into simple chains by an intermolecular C-Hpi interaction involving a phenyl beta-C atom as donor. Intramolecular C-Hpi interactions are also present.

Polymeric nanoparticle-encapsulated hedgehog pathway inhibitor HPI-1 (NanoHHI) inhibits systemic metastases in an orthotopic model of human hepatocellular carcinoma.[Pubmed:21868763]

Clin Cancer Res. 2012 Mar 1;18(5):1291-302.

PURPOSE: To illustrate the prognostic significance of hedgehog (Hh) signaling in patients with hepatocellular carcinoma (HCC) and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor, Gli1 (NanoHHI) using in vitro and in vivo models of human HCCs. EXPERIMENTAL DESIGN: Patched1 (Ptch1) expression was detected in tumor tissue microarrays of 396 patients with HCC who underwent curative surgical resection during February 2000 to December 2002. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. The effects of NanoHHI alone and in combination with sorafenib were investigated on HCC cell lines. Primary HCC tumor growth and metastasis were examined in vivo using subcutaneous and orthotopic HCC xenografts in nude mice. RESULTS: Elevated expression of Ptch1 in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in patients with HCC. In vitro, NanoHHI significantly inhibited the proliferation and invasion of HCC cell lines. NanoHHI potently suppressed in vivo tumor growth of HCC xenografts in both subcutaneous and orthotopic milieus, and in contrast to sorafenib, resulted in significant attenuation of systemic metastases in the orthotopic setting. Furthermore, NanoHHI significantly decreased the population of CD133-expressing HCC cells, which have been implicated in tumor initiation and metastases. CONCLUSION: Downstream Hh signaling has prognostic significance in patients with HCC as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and antimetastatic effects in HCC models, which may provide a new strategy in the treatment of patients with HCC and prevention post-operative recurrence.

Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade.[Pubmed:19666565]

Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14132-7.

Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate Hh pathway-dependent tumors. We report here four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused [Su(fu)], including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors. Each inhibitor has a unique mechanism of action, and their phenotypes reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable. We further establish the ability of certain compounds to block the proliferation of cerebellar granule neuron precursors expressing an oncogenic form of Smo, and we demonstrate that Hh pathway inhibitors can have tissue-specific activities. These antagonists therefore constitute a valuable set of chemical tools for interrogating downstream Hh signaling mechanisms and for developing chemotherapies against Hh pathway-related cancers.