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Reversible Covalent Kinase Inhibitors to Combat Metastasis

Institution: University of California, San Francisco
Investigator(s): Shyam Krishnan, Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19FT-0091 Award: $135,000
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Protein kinases are enzymes that transfer phosphate groups to proteins, and perform essential functions in cell growth and multiplication. Aberrant kinase activity is one of the important causes of the development of cancer, and many drugs have been developed with the aim of binding to such kinases and inhibiting their enzymatic activity with the goal of killing tumor cells, as well as preventing their spread or metastasis to other regions of the body. Most of the current kinase inhibitors bind to their targets without the formation of discrete covalent bonds between the inhibitor and the kinase. This is due to concerns of toxicity and lack of selectivity due to the possibility of reactive functional groups on the inhibitor irreversibly modifying off-target proteins. We will develop inhibitors that will form covalent bonds with their kinase targets, but do so in a reversible manner, such that the formed bond will break readily with off-target proteins, but remain long-lived with the targeted kinase. This will result in a drug with high selectivity for its target and therefore, low toxicity to patients. Sustained occupancy of the active site of the kinase with the drug due to covalent bond formation will also enable low dosages for patients. The RSK family of kinases has been shown to be a relevant target to prevent the metastasis of head and neck cancer. We have already developed an inhibitor that binds to the kinase RSK2 in a reversible manner. We will optimize this inhibitor for potency toward RSK2 as well as stability under physiological conditions, so that the compound can be advanced to the clinic for metastatic head and neck cancer treatment. We will accomplish this by using the tools of chemical synthesis to prepare derivatives of our initial lead compound, following by screening for RSK2 inhibition. We will also develop molecules with carbon-carbon double bonds bearing pairs of chemical functional groups that can serve to bind the thiols of cysteine residues of protein kinases in a reversible, covalent manner. We will prepare such molecules using chemical synthesis and test them for binding of thiols. Once we have a collection of such activated modules, we will attach them to molecular fragments that have been shown to bind protein kinases. This will allow us to prepare reversible covalent inhibitors of metastatic head/neck and lung cancer relevant kinases that are closely related by virtue of having a cysteine residue in the same region of the active site, such as RSK1-4, MSK1/2, and PLK1, which has been shown to be essential for cell division and has also been targeted in the treatment of solid tumors. Our goal is to develop inhibitors that can target combinations of these kinases, so that we can test the resulting compounds for their ability to kill cancer cells and prevent metastasis by utilizing the synergistic effects of targeting several of these enzymes concurrently. We will also investigate the effect of selective RSK inhibitors on the expression of genes that promote invasion and metastasis of head/neck and lung cancer cells, as well as test the requirement of RSK activity for metastasis in lung cancer.

The development of a selective, potent and stable inhibitor of RSK2 that is suitable for clinical investigation is likely to significantly enhance our ability to treat metastatic head and neck cancer. The development of molecular ‘modules’ capable of binding cysteine thiols in a reversible manner, and subsequently multi-targeted inhibitors directed toward kinases relevant to metastatic head/neck and lung cancer will allow the investigation of the synergistic effects of such potential drugs, and allow the interrogation of the functions of these enzymes in the spread of cancer cells from the original tumor. Drugs that act by reversible covalent binding to their kinase targets will likely require low dosages due to high potency, and also display less toxic side effects.

Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles
Periodical: Nature Chemical Biology Index Medicus:
Authors: Serafimova IM, Pufall MA, Krishnan S, et al ART
Yr: 2012 Vol: 8 Nbr: Abs: Pg: 471-476