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停止肿瘤的生长。过渡态理论正被用来设计针对特定酶的强效抑制剂。人5 '-甲硫腺苷磷酸化酶（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，在远远超过有效剂量时对小鼠无毒性。该抑制剂导致小鼠血液、组织和肿瘤中正常人代谢物5 '-甲硫基腺苷（MTA）的增加。MTAP的抑制可防止MTA再循环为S-腺苷甲硫氨酸（S-腺苷蛋氨酸）。对MTDIA具有抗性的人FaDu头颈癌细胞系显示MAT 2A区域的特异性扩增，MAT 2A区域是编码MAT IIa的基因，MAT IIa是癌症特异性的α-Met合成酶的催化亚基。本研究的目的是研究MTDIA抗癌作用在MTAP-MAT IIa界面的生化机制。MAT IIa被认为是抗癌靶点。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。MAT I/III同工酶的类似研究将探索过渡态特异性。 关于MTDIA作用机制的假设包括：1）MTAP抑制导致MTA的代谢积累; 2）MTA抑制MAT IIa以消耗线粒体Met并导致对肿瘤生长有害的下游变化; 3）MTA或MTDIA破坏MAT IIa与染色质相关蛋白的相互作用; 3）MTDIA或MTA改变MAT IIa或MAT IIb的表达，其调节亚基改变活性或辅阻遏物功能， 或4）MTA和/或MTDIA通过与转录因子的相互作用改变基因表达。由MTDIA治疗诱导的变化是令人感兴趣的，因为它们引起肿瘤的生长停滞，对宿主组织具有宽的安全范围。MAT活性的过渡态分析将为作为抗癌靶点的β-Met代谢的抑制剂设计提供蓝图。MTAP和MAT IIa是抗癌药物的新的、不断发展的靶点。MTDIA的抗癌作用机制将通过其对MAT IIa/B表达的影响和对MTA、MAT和MTDIA相互作用因子的亲和力探测来测试。过渡态类似物的低毒性和独特的作用机制使其成为癌症治疗中多药物组合的有希望的候选者。

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.