Significance: Melanoma is the deadliest form of skin cancer and represents a growing economic burden and health concern in the U.S. While early-stage melanoma can often be treated surgically, therapies for advanced forms of the disease are severely lacking. As rates of melanoma continue to rise, it is imperative that we develop novel and effective treatments for this disease. The most aggressive form of melanoma results from a mutation in the small GTPase NRas and presents in 20% of patients. While NRas is an attractive therapeutic target in melanoma, it has proven notoriously difficult to drug due to the lack of suitable binding pockets on its surface. This limitation has prevented the development of NRas-targeted therapies. Objective: To address the unmet need for NRas-targeted drugs, we will target a previously overlooked region of NRas, the S-palmitoylation of its C-terminal hypervariable region. Numerous studies have confirmed that NRas palmitoylation is required for its cancer signaling activity. To exploit this feature of NRas, we have developed a novel class of Depalmitoylating Molecules (DPALMs) which chemoselectively cleave S-palmitoyl groups from proteins in live cells. Preliminary Data: We have identified a set of DPALM lead compounds which preferentially depalmitoylate NRas in living cells. Furthermore, we found that DPALMs can inhibit downstream Ras signaling pathways and preferentially kill NRas-mutant versus non-NRas-mutant cell lines, highlighting their therapeutic potential.
Specific Aims : We will optimize the potency and selectivity of our lead compounds to generate a DPALM suitable for preclinical testing and IND enabling studies.
In SPECIFIC AIM 1, we will generate a set of optimized DPALMs using joint synthesis and screening efforts. A modular and robust synthetic strategy will be used to generate new compounds which will then be screened for NRas depalmitoylation activity and selectivity in a validated assay.
In SPECIFIC AIM 2, we will evaluate the efficacy of optimized DPALMs in NRas-driven melanoma cell lines. Compounds will be tested for their ability to preferentially inhibit growth and induce cell death in NRas-driven versus control cell lines. The proposed studies will enable the development of a highly NRas-selective DPALM and accelerate the commercialization of this targeted therapy for the treatment of melanoma and several other cancers with high rates of NRas-mutations.

Public Health Relevance

This proposal addresses the unmet need for NRas-targeted therapeutics for the treatment of metastatic melanoma. We will optimize the potency and selectivity of our lead small molecule inhibitors of NRas to maximize their efficacy in NRas-driven melanoma cells. This work will identify compounds suitable for in vivo evaluation and IND enabling studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43CA250702-01A1
Application #
10080443
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kamei, Nancy Uyeno
Project Start
2020-09-21
Project End
2021-08-31
Budget Start
2020-09-21
Budget End
2021-08-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Palm Therapeutics, Inc.
Department
Type
DUNS #
117013536
City
La Jolla
State
CA
Country
United States
Zip Code
92037