Structure-based Drug Design of Inhibitors for a Breast Cancer Signature Kinase Clinical identification of breast cancer subtypes allows for personalized treatment resulting in better outcomes. One subtype, basal-type breast cancer, is highly heterogeneous and associated with poor prognosis. Although it is not the most common form of breast cancer, its poor prognosis along with the lack of subtype specific treatments demand an increased focus on development of new therapies directed specifically at basal-type disease. Very recent studies implicate the protein kinase WNK1 as one of a handful of signature genes of basal-type breast cancer. Protein kinases are well-established drug targets i...

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Structure-based Drug Design of Inhibitors for a Breast Cancer Signature Kinase Clinical identification of breast cancer subtypes allows for personalized treatment resulting in better outcomes. One subtype, basal-type breast cancer, is highly heterogeneous and associated with poor prognosis. Although it is not the most common form of breast cancer, its poor prognosis along with the lack of subtype specific treatments demand an increased focus on development of new therapies directed specifically at basal-type disease. Very recent studies implicate the protein kinase WNK1 as one of a handful of signature genes of basal-type breast cancer. Protein kinases are well-established drug targets in the treatment of cancer and other diseases. The Goldsmith laboratory has discovered novel WNK1 small molecule inhibitors and obtained the atomic structure of WNK1 bound to these molecules, allowing visualization of their interactions. The Tambar laboratory is expert in medicinal chemistry with a track record in cancer-directed synthesis programs. To address the unmet clinical need of effective therapies for basal-type breast cancer, we propose to develop a new class of inhibitors for WNK1, a kinase target for which no approved drugs are available. These studies will provide a foundation for our long-term goal of developing a drug candidate. The collaboration between the two labs will focus on the structure-guided design of WNK1 inhibitors that will be informed by crystallography and chemical synthesis. We will improve our initial compounds to generate more specific and potent WNK1 inhibitors, and test them as drugs targeted to basal-type breast cancers. We will then employ primary tumors to test efficacy of our improved inhibitors. With sufficient efficacy and bioavailability, these molecules will be potential chemotherapeutic drugs targeted against basal-type breast cancers.

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