3:59 PM
Dec 04, 2018
 |  BC Extra  |  Preclinical News

Yumanity reveals Parkinson's candidate as first compound from yeast platform

Yumanity Therapeutics LLC (Cambridge, Mass.) and colleagues used the company's yeast platform to identify inhibitors of the enzyme stearoyl-CoA desaturase-1 (SCD1) that could prevent α-synuclein toxicity in Parkinson's disease. The SCD1 inhibitors are the first compounds Yumanity has disclosed from its yeast discovery platform. The company plans to enter the clinic with lead SCD1 inhibitor, YTX-7739, in 4Q19 to treat PD.

In a paper published in Cell Reports Tuesday, the team showed that the SCD1 inhibitors decreased α-synuclein toxicity and increased cell growth in the yeast model. In a human induced pluripotent stem cell (iPSC)-derived neuronal model of α-synuclein toxicity, an SCD1 inhibitor increased survival compared with vehicle. The compounds rescued α-synuclein toxicity by reducing levels of unsaturated fatty acids, which the authors think prevented overexpressed α-synuclein from binding to membranes and disrupting lipid vesicle trafficking that leads to α-synuclein aggregation and neurodegeneration.

Yumanity Chairman and CEO Tony Coles and the late Susan Lindquist launched the company in 2014 based on the work of Lindquist, who had built a suite of yeast-based tools for finding targets related to protein misfolding. Lindquist was a professor at the Massachusetts Institute of Technology and former director of the Whitehead Institute for Biomedical Research. Yumanity's discovery platform involves engineering yeast to overexpress misfolded proteins that are known to play central roles in neurological diseases. The company then screens compound libraries in the yeast and looks for molecules that rescue cell growth. Hits can be tested to see if they rescue mammalian cells, or their mechanism of action explored in the yeast (see "Yeast on the Brain").

Author and Yumanity CSO Kenneth Rhodes told BioCentury the company plans to disclose additional targets emerging from its α-synuclein, apolipoprotein E epsilon 4 (APOE4) and other proteinopathy programs at a later date.

A second paper published Tuesday in Molecular Cell by Lindquist's colleagues at Harvard Medical School and Whitehead Institute supported the findings and connected SCD1 inhibitors with the unsaturated fatty acid oleic acid. The team found that yeast overexpressing α-synuclein also had increased levels of oleic acid, which increased α-synuclein toxicity. Inhibitors of SCD1, which produces oleic acid, decreased α-synuclein toxicity and increased cell survival in the yeast and in rat neuronal models and decreased phosphorylated α-synuclein in human neurons.

Rhodes said Yumanity is now collaborating with the Harvard team to advance the SCD1 inhibitors.

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