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Mar 21, 2016
 |  BioCentury  |  Emerging Company Profile

Targeting toxicity

Novonco ribonucleotide reductase, HMT inhibitors could be safer than predecessors

Novonco Therapeutics Inc. is developing a pipeline of targeted cancer therapies that were designed at City of Hope and University of California Irvine to be less toxic than either first-generation inhibitors, or parent molecules.

Its lead compound is COH29, a small molecule ribonucleotide reductase inhibitor that is slated to enter Phase I testing this year in solid tumors.

Ribonucleotide reductase catalyzes the formation of deoxyribonucleotide triphosphates (dNTPs) that support DNA synthesis and tumor proliferation. The enzyme is the target of marketed drugs including hydroxyurea and gemcitabine. But these drugs are limited by side effects including myelosuppression and gastrointestinal, dermatologic and pulmonary toxicities.

City of Hope researchers used a structure-based approach to design COH29 to bind its target differently than hydroxyurea and gemcitabine do. The molecule interferes with the interaction between ribonucleotide reductase's protein subunits - ribonucleotide reductase M1 (RRM1; R1) and RRM2 - by targeting a novel binding pocket on RRM2.

Hydroxyurea targets a different binding pocket on RRM2. Gemcitabine targets RRM1 and DNA...

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