Anthony Estrada 

Vitals

Current Affiliation: Denali Therapeutics

Age: 35

Ph.D. alma mater: University of California, San Diego

Role model: former UCLA head coach John Wooden. “He has taught me to always be prepared, to pay attention to details, and to be a realistic optimist.”

Advice for young scientists: “As a scientist you will inevitably fail far more times than you will succeed. If you are not making mistakes, then you are not doing anything. Run the experiment!”

Codename: Med Chem Marksman

Anthony Estrada prides himself on never being outworked. A relic from his college basketball days, that fierce determination has taken on new weight as he tries to tackle the most notoriously tough area of drug discovery: neuroscience.

It was while still focused on college basketball that Estrada first discovered chemistry. After seeing his high school grades, a counselor at the University of La Verne matched him with chemistry professor Namphol Sinkaset. “I was in his office 24/7, asking to do experiments, talking about chemistry nonstop,” Estrada recalls of his undergrad adviser.

Sinkaset introduced him to famed organic chemist K.C. Nicolaou’s “Classics in Total Synthesis.” Reading the textbook, Estrada was so taken with the idea of building complex molecules that after college he joined Nicolaou’s lab at the University of California, San Diego.

Former UCSD labmates remember Estrada as “a rock star” grad student who played a critical role in cracking the synthesis of thiostrepton, an antibiotic with a whopping 10 rings, 11 peptide bonds, and 17 stereogenic centers.

Estrada then went straight to a job at Genentech, where he soon landed in the neuroscience group. It was a good fit: The knotty problem of designing molecules to overcome the biological, physical, and chemical challenges of the brain was perfect for the determined chemist.

At Genentech, Estrada worked on small molecules to block LRRK2, a protein that so far has the best-known genetic ties to Parkinson’s disease. The series of compounds is now helping elucidate the role of the protein and inform future drug discovery efforts.

Last year, Estrada jumped to Denali Therapeutics, a closely watched biotech started by an elite crew of Genentech scientists. Denali is taking fresh approaches to Alzheimer’s, Parkinson’s, and ALS—diseases that have stymied even the best drug hunters. Estrada is undaunted. The resiliency he learned in sports is keeping him focused on overcoming the industry’s earlier failures, he says: “I don’t give up.”

Research at a glance

Estrada and his colleagues at Genentech designed compounds that target the Parkinson’s disease-linked protein LRRK2. To sneak these inhibitors (some shown here) past the blood-brain barrier, the researchers had to build them so they balanced opposing needs: metabolic stability, which often requires spreading polarity across a molecule, and equal brain distribution, which favors nonpolar molecules. Credit: Shutterstock/C&EN

Estrada and his colleagues at Genentech designed compounds that target the Parkinson’s disease-linked protein LRRK2. To sneak these inhibitors (some shown here) past the blood-brain barrier, the researchers had to build them so they balanced opposing needs: metabolic stability, which often requires spreading polarity across a molecule, and equal brain distribution, which favors nonpolar molecules. Credit: Shutterstock/C&EN

Three key papers:

“Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors” (J. Med. Chem. 2014, DOI: 10.1021/jm401654j)

“Pyrimidoaminotropanes as Potent, Selective and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)” (J. Med. Chem. 2013, DOI: 10.1021/jm400194n)

“Discovery of Highly Potent, Selective and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors” (J. Med. Chem. 2012, DOI: 10.1021/jm301020q)

 

Career paths:

They might be young scientists, but our Talented 12 have already traveled far and wide.

anthony_estrada_map

Story in C&EN about Estrada’s work:

Thiostrepton from Scratch

 


Watch Estrada talk about his research during a special Aug. 22 Talented 12 symposium held at the American Chemical Society national meeting in Philadelphia.

Karena Chapman 
Daniel Fitzpatrick
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