Precision medicine: The right treatment for the right patients at the right time.
Novonco’s three platform technologies, all based on natural products, are the result of years of investigation into the medicinal chemistry and cancer biology of various tumors. These molecularly-targeted drugs represent the next generation of cancer therapies, offering hope to patients with limited treatment options, including those with acute myelogenous leukemia, ovarian and pancreatic cancers.
Targeting Ovarian and Other Hard-to-treat Cancers
COH29: A Novel Small Molecule Inhibitor of Ribonucleotide Reductase (RR) and DNA Repair
Novonco has teamed with City of Hope to bring COH29–a potential breakthrough in the fight against hard-to-treat cancers, including ovarian cancer–to clinical trials. The small molecule, COH29, inhibits the production of ribonucleotide reductase (RNR), an enzyme that is central to production of many types of cancer cells.
In preclinical studies, COH29 has been shown to reduce tumor growth in human cancers, including leukemia and ovarian cancer — diseases that are hard to treat, and it has also shown promise against breast cancer cells, and demonstrates potent antitumor activity against BRCA1-deficient ovarian cancer. First-in-human Phase I clinical trials of COH 29, are scheduled to begin in the fall of 2015, at City of Hope.
Ovarian cancer (OC) is the most lethal–and the second most common–gynecologic cancer in the United States, with over 20,000 new cases and 14,000 deaths expected yearly. Most of the cases are diagnosed at an advanced stage, with a corresponding 5-year survival rate of only 27 percent. Today, primary treatment of OC typically consists of surgery followed by first-line chemotherapy with a platinum/taxol combination.
While there are clinically-established RNR inhibitors–such as hydroxyurea and gemcitabine—on the market, they have drawbacks, including a short half-life and drug resistance. But COH29 represents a new class of RNR inhibitors, with unique targeted-action mechanisms that limit damage to non-cancer cells, thus limiting side effects. It can overcome hydroxyurea- and gemcitabine-resistance in cancer cells and may serve as a first or second line treatment in relevant cancers. This novel therapeutic agent has been in development at The City of Hope NCI-Designated Comprehensive Cancer Center and Beckman Research Institute.
COH29: Novel RR and DNA Repair Inhibitor
- Cancer requires ribonucleotide reductase (RR) to replenish deoxynucleotide triphosphates caused by damage from radiation and chemotherapy.
- COH29 blocks RR activity — preventing cancer cells from copying their DNA and stopping them from multiplying.
- COH29 further enhances the effectiveness of cisplatin, a common chemotherapy drug through DNA repair inhibition.
- City of Hope submitted an Investigational New Drug (IND) application and will be testing this new therapy with patients in phase I clinical trials in early 2016.
Zhou, B.; Su, L.; Hu, S.; Hu, W.; Yip, M. L. R.; Wu, J.; Gaur, S.; Smith, D. L.; Yuan, Y.-C.; Synold, T. W.; Horne, D.; Yen, Y
Cancer Res. 2013, 73, 6484-6493.
Chen M.-C.; Zhou B.; Zhang K.; Yuan, Y. C.; Un, F.; Hu, S.; Chou C.-M.; Chen, C-H.; Wu, J.; Wang, Y.; Liu, X.;
Smith, D. L.; Li, H.; Liu, Z.; Warden, C. D.; Su, L.; Malkas, L. H.; Chung, Y. M.; Hu, Mickey C.-T.; Yen, Y.
Mol. Pharm. 2015, 87, 996-1005.
An Epigenetic Therapy with the Potential to Treat Pancreatic Cancer
NV10: A Novel Small Molecule Inhibitor of Histone Methyltransferase SUV39H1
Histone Methyltransferases (HMTs) are a class of epigenetic enzymes which add methyl groups to histones. At least 22 out of the approximately 50 known human HMTs have been associated with cancer and other diseases.
Novonco scientists synthesized a series of novel epipolythiodioxopiperazines (ETPs) –a class of structurally complex natural products produced by fungi– testing each for anti-cancer properties and the ability to inhibit the enzymatic activity of a variety of HMTs. They found that one of these analogs, NV10, elicits broad and potent anticancer activity in vitro and in vivo in several cancer cell lines including hepatocelluar carcinoma and acute myeloid leukemia.
SUV39H1 is an enzyme that controls the expression of DNA. It’s been implicated in numerous cancers in various studies, including: Pancreatic, lung, liver, acute myeloid leukemia and multiple myeloma. NV10 was also shown to selectively inhibit SUV39H1 both in vitro and in vivo.
NV10 demonstrates compelling therapeutic potential in pancreatic cancer , selectively decreases viability of pancreatic cancer cells, but does not significantly affect viability of normal cell. NV10 also significantly decreases tumor volume in melanoma and lung cancer.
M. Baumann, A. P. Dieskau, B. M. Loertscher, M. C. Walton, S. Nam, J. Xie, D. Horne, and L. E. Overman
Chemical Science, 2015, 6, 4451–4457
Precision Medicine Rooted in Nature
A protein kinase is an enzyme that modifies other proteins by chemically adding a phosphate group. Phosphorylation can lead to some cancers and inflammatory diseases.
Indirubin: An active anticancer component of the Traditional Chinese Medicine (TCM) Dang Gui Long Hui Wan
Novonco is developing a new class of selective kinase inhibitors for personalized medicine in molecularly-targeted therapeutics for solid and hematologic malignancies. The new class of inhibitors are derived from the natural product, indirubin, which has long been used in Traditional Chinese Medicine, Dang Gui Long Hui Wan, for the treatment of chronic myelogenous leukemia (CML).
New indirubin analogs have been synthesized to expand and greatly enhance their therapeutic potential to solid tumors such lung cancers and relapsed acute mylogenous leukemia with FLT3 mutations. Recent studies have also shown that indirubins may improve survival in glioblastoma by blocking tumor-cell invasion and angiogenesis.
In combination with ETP therapeutics, indirubin shows remarkable synergistic activity and novel mechanism of action.