A goal of cancer therapy is to stop growth of tumors with minimal effects on normal cells. Transition state theory is being used to design powerful inhibitors for specific enzymes. A transition state analogue (MTDIA) of human 5'-methylthioadenosine phosphorylase (MTAP) inhibits growth of human lung, breast, prostate, colon and head and neck cancers in mouse xenografts. The inhibitor is orally available and shows no toxicity against mice far in excess of effective doses. The inhibitor causes an increase in the normal human metabolite 5'- methylthioadenosine (MTA) in mouse blood, tissues and tumors. Inhibition of MTAP prevents MTA recycling to S-adenosylmethionine (AdoMet). Human FaDu head and neck cancer cell lines made resistant to MTDIA show specific amplification of the MAT2A region, the gene encoding MAT IIa, the catalytic subunit of the cancer- specific AdoMet synthetase. Goals of this research are to investigate the biochemical mechanism of action of MTDIA anticancer effects at the MTAP-MAT IIa interface. MAT IIa is implicated as an anticancer target. The MAT IIa transition state structure will be established to foster design of transition state analogues in this novel anticancer pathway. Similar studies with the MAT I/III isozymes will explore transition state specificity. Hypotheses for the MTDIA mechanism of action include: 1) MTAP inhibition causes metabolic accumulation of MTA;2) MTA inhibits MAT IIa to deplete AdoMet and cause downstream changes detrimental to tumor growth;3) MTA or MTDIA disrupt MAT IIa interactions with chromatin-related proteins;3) MTDIA or MTA alter the expression of MAT IIa or MAT IIb, its regulatory subunit to alter activity or corepressor function, or that 4) MTA and/or MTDIA alter gene expression by interaction with transcription factors. The changes induced by MTDIA treatment are of interest as they cause growth arrest of tumors with a wide margin of safety for host tissues. Transition state analysis of MAT activity will provide a blueprint for inhibitor design of AdoMet metabolism as an anti-cancer target. MTAP and MAT IIa are new, evolving targets for anti-cancer agents. The mechanism of anticancer action for MTDIA will be tested by its effects on MAT IIa/b expression and affinity probing for MTA, MAT and MTDIA interacting factors. The low toxicity and unique mechanism of action of the transition state analogue makes it a promising candidate for multi-drug combinations in cancer therapy.
A new anticancer agent called MTDIA shows powerful anticancer effects in animal models of human lung, breast, prostate, colon and head and neck cancers. It does not cause side effects. Human genome studies suggest that MTDIA exerts its action by altering a normal pathway human metabolism. This research will establish how the anticancer activity of MTDIA works in human cells and will use that information to discover a second-generation of anticancer drugs with few side effects.
|Schramm, Vern L (2013) Transition States, analogues, and drug development. ACS Chem Biol 8:71-81|
|Burgos, Emmanuel S; Gulab, Shivali A; Cassera, Maria B et al. (2012) Luciferase-based assay for adenosine: application to S-adenosyl-L-homocysteine hydrolase. Anal Chem 84:3593-8|
|Basu, Indranil; Locker, Joseph; Cassera, Maria B et al. (2011) Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5'-methylthioadenosine phosphorylase. J Biol Chem 286:4902-11|
|Hemeon, Ivan; Gutierrez, Jemy A; Ho, Meng-Chiao et al. (2011) Characterizing DNA methyltransferases with an ultrasensitive luciferase-linked continuous assay. Anal Chem 83:4996-5004|
|Guan, Rong; Ho, Meng-Chiao; Brenowitz, Michael et al. (2011) Entropy-driven binding of picomolar transition state analogue inhibitors to human 5'-methylthioadenosine phosphorylase. Biochemistry 50:10408-17|
|Schramm, Vern L (2011) Enzymatic transition states, transition-state analogs, dynamics, thermodynamics, and lifetimes. Annu Rev Biochem 80:703-32|