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The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers.

ABSTRACT: Microtubule targeting agents are among the most widely used chemotherapeutics for both solid and hematological malignancies. This study characterizes the diaryl-oxazole based anticancer agent PC-046, which was originally identified for development based on selective activity in deleted in pancreas cancer locus 4 (DPC4/SMAD4) deficient tumors. PC-046 has growth inhibitory activity in a variety of tumor types in vitro, and efficacy in SCID mice was shown in human tumor xenografts of MV-4-11 acute myeloid leukemia, MM.1S multiple myeloma, and DU-145 prostate cancer. Pharmacokinetic studies demonstrated relatively high oral bioavailability (71%) with distribution to both plasma and bone marrow. No myelosuppression was seen in non-tumor bearing SCID mice given a single dose just under the acute lethal dose. The COMPARE algorithm in the NCI-60 cell line panel demonstrated that PC-046 closely correlated to other known tubulin destabilizing agents (correlation coefficients ≈0.7 for vincristine and vinblastine). Mechanism of action studies showed cell cycle arrest in metaphase and inhibition of tubulin polymerization. Overall, these studies show that PC-046 is a synthetically-derived, small molecule microtubule destabilizing agent. Advantages over existing microtubule destabilizing agents include ease of synthesis, lack of MDR cross-resistance, good oral bioavailability and the lack of acute myelotoxicity.

SUBMITTER: Landowski TH

PROVIDER: S-EPMC3899824 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers.

Landowski Terry H TH Samulitis Betty K BK Dorr Robert T RT

Investigational new drugs 20130914 6

Microtubule targeting agents are among the most widely used chemotherapeutics for both solid and hematological malignancies. This study characterizes the diaryl-oxazole based anticancer agent PC-046, which was originally identified for development based on selective activity in deleted in pancreas cancer locus 4 (DPC4/SMAD4) deficient tumors. PC-046 has growth inhibitory activity in a variety of tumor types in vitro, and efficacy in SCID mice was shown in human tumor xenografts of MV-4-11 acute ...[more]

PMID: 24037082

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Project description:BackgroundThe present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias.MethodsLiterature searches produced about 2500 epidemiology and basic science articles related to the BRCA pathway. These articles were reviewed and copied to a database to facilitate access. Meta-analyses of statistical information compared risks for hematologic cancers vs. mutations for the components in a model pathway containing BRCA1/2 gene products.ResultsDeleterious mutations of genes encoding proteins virtually anywhere within the BRCA pathway increased risks up to nearly 2000 fold for certain leukemias and lymphomas. Cancers with large increases in risk included mantle cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and prolymphocytic leukemia. Mantle cell lymphoma is defined by a characteristic rearrangement of DNA fragments interchanged between chromosomes 11 and 14. DNA translocations or rearrangements also occur in significant percentages of the other cancers.ConclusionAn important function of the BRCA pathway is to prevent a subgroup of human leukemias and lymphomas that may involve non-random, characteristic gene rearrangements. Here, the genetic defect in BRCA pathway deficiencies is a chromosomal misrepair syndrome that may facilitate this subgroup of somatic cancers. Inactivation of a single gene within the pathway can increase risks for multiple cancers and inactivation of a different gene in the same pathway may have similar effects. The results presented here may have clinical implications for surveillance and therapy.

Project description:AbstractIn an earlier publication, a binary classification of chronic diseases has been proposed. Chronic diseases were classified as “high Treg” or “low Treg” diseases depending on whether the pro-inflammatory or the anti-inflammatory arms of the immune response are deficient. The present work uses this model to analyze the interplay between cancer and the immune system, based on published literature. The work leans upon the etiology of alcohol and tobacco-related malignancies. The main conclusions are: triggers of specific “high Treg” immune reaction promote most non-hematologic cancers, whereas triggers of “low Treg” immune reaction promote lymphomas. The opposite is also true: triggers of specific “high Treg” immune reaction suppress lymphoma, whereas triggers of “low Treg” immune reaction suppress non-hematologic cancers. Both lymphoma and autoimmune diseases are “low Treg” conditions. For this reason, both are promoted by the same panel of “low Treg” bacteria and parasites and are inhibited by “high Treg” triggers. For example, alcohol consumption, a “high Treg” trigger, protects against lymphoma and autoimmune hypothyroidism. In addition, the same immune-modulatory drugs are effective in the treatment of both lymphoma and autoimmune diseases. Like other cancers, lymphoma transforms from a “low Treg” type at early stage of the disease into a “high Treg” type at advanced stages. However, lymphoma is distinguished from most other cancers by the length of time it dwells at an indolent “low Treg” state (many years) before lymphoma cells sensitivity to transforming growth factor-beta is impaired. This impairment stimulates the switch from “low Treg” into “high Treg” response and results in immune escape. The application of this analysis to the pharmacological activity of checkpoint inhibitors forecasts that checkpoint inhibitors would not be effective in low-grade, indolent lymphomas. As of now, checkpoint inhibitors are approved for the treatment of advanced lymphoma only.

Dataset Information

The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers.

Publications

The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers.

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