Shahienaz Hampton, a postdoctoral associate in the Dore Lab at NYU Abu Dhabi, is part of a team investigating Ras proteins, which function as molecular switches and are involved in transmitting signals within cells. When Ras is switched on, this subsequently turns on genes involved in cellular processes including cell growth and cell proliferation. Consequently, mutations in Ras genes, also known as oncogenes, result in the production of overactive Ras that may ultimately lead to cancer. As such, oncogenic Ras is implicated in and accounts for approximately 20 percent to 30 percent of human cancers, primarily pancreatic and colon cancers.
Ras possesses a four-amino acid sequence at one end of the protein, known as the "CaaX box." This undergoes a set of post-translational modifications, an alteration to the protein that is required to target Ras to the cell membrane.
The Ras converting enzyme (Rce1), a CaaX protease and an integral membrane protein, is one of the key modifying enzymes required in the maturation of Ras, causing it to be functionally active.
Hampton's current study targets this enzyme. "Our aim is to inhibit Rce1 so that Ras is unable to be correctly modified," she explained. "Subsequently, this may block the association of Ras to the cell membrane. As a medicinal chemist, I design and synthesize compounds with my colleague Idrees Mohammed, which hopefully will bind and perturb the enzyme's functionality."
The process starts with molecules that reduce the enzyme's activity, known as "hit compounds," which were identified as a result of a high-throughput chemical screen. Individual changes may then be made around the core of the compounds. This gives an insight into what modifications increase or decrease the activity of the enzyme, known as the structure-activity relationship (SAR).
"So far, we have managed to obtain moderate activity against this enzyme with our small molecule inhibitors. We are very pleased about this," Hampton said. "We are hoping to increase potency of these compounds toward Rce1, and we would also like to improve selectivity against the functionally similar zinc metalloprotease, ZMPSTE24, also a proteolytic enzyme."
In the absence of the correct post-translational modifications, Ras is unable to localize to the cell membrane, thus resulting in mislocalised Ras and defective Ras signaling. Therefore inhibition of Ras maturation is considered to be a potential anticancer strategy.
This article originally appeared in NYUAD's 2013-14 Research Report (13MB PDF).