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Lehi, UT, United States

Bearss D.J.,Tolero Pharmaceuticals, Inc.
Science Translational Medicine

A nanoparticle formulation of an Aurora B inhibitor increases antitumor efficacy and reduces toxicity, which may be a precedent for the use of this technology with other small molecules (Ashton et al., this issue). Source

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2012

TP-0413 is a novel small molecule inhibitor of the BMP pathway that has significant potential to be developed to treat anemia of cancer. Anemia of cancer is cytokine driven and results in the up-regulation of a liver hormone called hepcidin through the function of BMP receptors. Increased hepcidin levels result in the storage of iron in cellular compartments resulting in low serum iron and anemia. Anemia of cancer is a significant health issue in a majority of cancer patients and is currently only treatableby blood transfusion. As an inhibitor of BMP signaling, TP-0413 has shown promise in cell-based and animal models. TP-0413 inhibits cytokine signaling and raises serum iron and red blood cells in mouse models of anemia. Ideally, TP-0413 will be developedas an oral agent and to this end, the studies described in this proposal aim at identifying and optimizing a pharmaceutical salt form of the compound that is orally available with enhanced efficacy. Furthermore, five-day repeat dose toxicity studies will be performed in rats in preparation for choosing a dose and schedule for GLP toxicity studies. The overarching goal of this work is to develop an optimized oral agent for the treatment of anemia in cancer.

Tolero Pharmaceuticals, Inc. | Date: 2013-10-16

Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R3, R4, R5 and R6 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

SALT LAKE CITY--(BUSINESS WIRE)--Tolero Pharmaceuticals, Inc., a clinical-stage company developing treatments for serious hematological diseases, and Eutropics, Inc. (Cambridge, MA), a clinical diagnostic company, announced today the details of a biomarker-driven clinical development strategy for the CDK9 inhibitor, alvocidib, in patients with acute myeloid leukemia (AML). The analysis of clinical samples utilized Eutropics’ novel companion diagnostic platform, PraediCare Dx, to analyze bone marrow to determine if a single marker was enriched in patients who went on to achieve a complete remission after treatment with an alvocidib-containing regimen. The results from this analysis demonstrated that patients whose bone marrow samples had high activity levels of the pro-apoptotic protein, NOXA, were most likely to attain a complete remission from the alvocidib regimen. These findings were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. The analysis of NOXA sensitivity may be used to further support the development of alvocidib, which has demonstrated compelling clinical activity in patients with AML when combined with standard chemotherapy agents, such as cytarabine and mitoxantrone. The companies plan to validate the patient enrichment strategy of using Eutropics’ companion diagnostic test as a way to identify patients with a very high probability of attaining a complete remission when treated with alvocidib-based regimens. “High NOXA sensitivity in these patients samples strongly correlated with the patient achieving a complete remission on alvocidib-based treatment. This analysis may provide a powerful tool to ensure that patients treated with alvocidib have a greatly increased potential to achieve a complete remission and potentially enjoy a positive long-term outcome,” said David J. Bearss, PhD, CEO of Tolero. “Furthermore, the link of NOXA sensitivity to the function of MCL-1 further substantiates the clinical mechanism of action of alvocidib through CDK9-dependent suppression of MCL-1 expression, a major signaling pathway in the biology of AML.” “The PraediCare Dx platform demonstrated strong predictive power in this analysis and further supports our goals to make sure patients are matched to the right therapies that will benefit them the most,” said Michael Cardone, PhD, CEO of Eutropics. Alvocidib is a potent small molecule inhibitor of cyclin-dependent kinases (CDKs) in development as a combination therapy for frontline and relapsed/refractory AML. CDKs are regulatory proteins that are critical to cellular replication and regulation of gene expression. Given the key role CDK de-regulation plays in unchecked cell division, proliferation and expression of cancer-associated genes, CDKs are an attractive target for the treatment of various cancers. Eutropics is a clinical diagnostics company that is utilizing a novel approach for guiding the use of established and experimental therapeutics, enabling the delivery of personalized medicines to patients suffering from cancer. Eutropics' PraediCare Dx platform delivers medically useful CLIA certified in vitro diagnostic assays. Eutropics (www.eutropics.com) is a privately held company located in Cambridge, MA. Tolero Pharmaceuticals is a clinical stage biopharmaceutical company developing treatments to improve and extend the lives of patients with serious oncological and hematological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias and anemia as well as important targets of drug resistance and transcriptional control.

DUBLIN--(BUSINESS WIRE)--Research and Markets (http://www.researchandmarkets.com/research/6k32tq/chemotherapy) has announced the addition of the "Chemotherapy Induced Anemia - Pipeline Review, H1 2015" report to their offering. This report provides comprehensive information on the therapeutic development for Chemotherapy Induced Anemia, complete with comparative analysis at various stages, therapeutics assessment by drug target, mechanism of action (MoA), route of administration (RoA) and molecule type, along with latest updates, and featured news and press releases. It also reviews key players involved in the therapeutic development for Chemotherapy Induced Anemia and special features on late-stage and discontinued projects. The report enhances decision making capabilities and help to create effective counter strategies to gain competitive advantage. It strengthens R&D pipelines by identifying new targets and MOAs to produce first-in-class and best-in-class products.

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