Methylthioadenosine Phosphorylase and AdoMet Synthetase in Cancer

描述（由申请人提供）：癌症治疗的目标是在对正常细胞影响最小的情况下阻止肿瘤的生长。过渡态理论被用于设计针对特定酶的强效抑制剂。人5'-甲基硫代腺苷磷酸化酶（MTAP）的过渡态类似物（MTDIA）抑制小鼠异种移植物中人肺癌、乳腺癌、前列腺癌、结肠癌和头颈癌的生长。该抑制剂可口服，对小鼠没有毒性，远远超过有效剂量。该抑制剂引起小鼠血液、组织和肿瘤中正常人体代谢物5'-甲基硫代腺苷（MTA）的增加。抑制MTAP可防止MTA再循环为s -腺苷蛋氨酸（AdoMet）。对MTDIA产生抗性的人FaDu头颈部癌细胞系显示出MAT2A区域的特异性扩增，该区域是编码癌症特异性AdoMet合成酶的催化亚基MAT IIa的基因。本研究旨在探讨MTDIA在mtap - matiia界面抗癌作用的生化机制。matiia被认为是一个抗癌靶点。将建立MAT IIa过渡态结构，以促进这种新型抗癌途径中过渡态类似物的设计。对MAT I/III同工酶的类似研究将探索过渡态特异性。关于MTDIA作用机制的假说包括：1)MTAP抑制导致MTA代谢积累；2) MTA抑制MAT IIa消耗AdoMet，引起不利于肿瘤生长的下游变化；3) MTA或MTDIA破坏matiia与染色质相关蛋白的相互作用；3) MTDIA或MTA改变其调控亚基MAT IIa或MAT IIb的表达，从而改变其活性或辅抑制因子功能；

DESCRIPTION (provided by applicant): 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.