Tryptase, a mast cell serine protease, has been implicated in the pathophysiology of allergic asthma, but formal evidence to support this hypothesis has been limited by the lack of specific inhibitors for use in vivo. Therefore, in this study we examined the effects of two inhibitors of tryptase, APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-prolinamide hydrochloride] and BABIM [bis(5-amidino-2-benzimidazolyl)methane] on antigen-induced early and late responses, airway responsiveness as measured by carbachol provocation, microvascular permeability as measured by bronchoalveolar lavage (BAL) albumin concentrations, and tissue eosinophilia from biopsies in allergic sheep. APC 366 and BABIM were administered by aerosol in all experiments. In vehicle control trials, antigen challenge resulted in peak early and late increases in specific lung resistance (SRL) of (mean +/- SE, n = 6) 259 +/- 30% and 183 +/- 27% over baseline, respectively. Treatment with APC 366 (9 mg/3 ml H2O given 0.5 h before, 4 h after, and 24 h after antigen challenge) slightly reduced the peak early response (194 +/- 41%), but significantly inhibited the late response (38 +/- 6%, p < 0.05 versus control trials). Twenty-four hours after challenge, APC 366 also completely blocked the antigen-induced airway hyperresponsiveness to inhaled carbachol observed in the control trial.(ABSTRACT TRUNCATED AT 250 WORDS)
Purpose: PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies.Experimental Design: Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low K m for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context.Results:LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model. Conclusions:We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies.
We have previously identified sequences required for thyroid hormone (T3) induction of the rat GH (rGH) promoter, which lie in a region from -188 to -164 upstream of the mRNA start site. Within this region, Domains A, -189 to -184 and B, -179 to -174, are imperfect direct repeats, and domain C, -172 to -167, is a divergent inverted copy that matches the A domain at 4/6 positions. A series of synthetic mutant versions of this sequence were inserted upstream of a truncated rGH promoter, or as a replacement for wild-type sequences in a synthetic 237 base pair rGH promoter or upstream of the heterologous thymidine kinase promoter. Mutations changing the B domain to a perfect copy of the A domain significantly increased T3 induction (21.3-fold) relative to the wild type (3.6-fold). A single point mutation making the C domain a better match to the A domain also increased T3 induction to 16.2-fold. Combining this up-mutation with any of three down-mutations in the A, B, or C domains strongly decreased response, showing that all three domains contribute to the amplified T3 response. Binding affinity of the various mutant oligonucleotides was assessed using in vitro translated receptor and affinity paralleled the functional responses for most binding site mutations. Requirements for in vitro binding were, however, less rigorous than those for functional T3 induction. Based on these results, we propose a consensus T3 receptor binding half-site, AGGT(C/A)A, at least two copies of which are required for a T3 response.(ABSTRACT TRUNCATED AT 250 WORDS)
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