Walker

Research

Repurposing Enzymes to Construct Biocatalysis Pathways toward Non-natural Bioactive Compounds

The Walker Group Research Topics

Biocatalysis of Docetaxel (Link to Intellectual Property: App. No. 15/671882)

▪ Taxane analogs (docetaxel, paclitaxel, cabazitaxel, paclitaxel C, and tesetaxel) are used 1) for breast, ovarian, and prostate cancers, 2) to stem complications from stent implants in heart surgery, and 3) to work potentially as neuroprotectants against stroke.


Importance of Docetaxel Chemotherapy

Docetaxel in Combination Drug Therapy in Independent Clinical Trials

▪ Triple-Negative Breast Cancer Type-4 shows a significant predictive value of response treated with docetaxel and carboplatin. Annals of Oncology 2017, 28, mdx362.013-mdx362.013.

▪ Pertuzumab is use in combination with trastuzumab and docetaxel in adult patients with HER2-positive breast cancer. The Lancet Oncology 2013, 14, 461-471.

▪ Nanotherapeutic (MM-310) delivery is antibody-directed and encapsulates a docetaxel prodrug, targeted to Ephrin receptor A2, that prolonged docetaxel exposure to the tumor with decreased exposure of normal tissues. Cancer Res 2017, 77 (13 Supplement) 3096.

 


Current 11-Step Method for Semisynthesis of Docetaxel (Taxotere®)

Access to bioactive taxanes still use a lengthy 11-12-step semisynthesis, including redundant protecting group manipulations, pyrophoric reagents/solvents, and heavy metals.

Proposed 3-Step Biocatalysis of a Docetaxel Intermediate from 10-Deacetylbaccatin III

Streamlined 3-Step Biocatalysis of Docetaxel: As an alternative to make docetaxel, we use regioselective biocatalysts (Taxus Acyltransferases (AT) of the BAHD Superfamily and Bacterial CoA Ligases) that bypass protecting group chemistry, eliminate heavy metal catalysts, and limit the use of petroleum-based solvents.

Coupling acyltransferases with CoA ligases (below) provides a Green source of a taxane drug precursor.