Methylthioadenosine Phosphorylase and AdoMet Synthetase in Cancer

描述(申请人提供)：癌症治疗的一个目标是在对正常细胞影响最小的情况下阻止肿瘤的生长。过渡态理论正被用来设计针对特定酶的强大抑制剂。人5‘-甲基硫代腺苷磷酸化酶(MTAP)的过渡态类似物(MTDIA)可抑制小鼠移植瘤中人肺癌、乳腺癌、前列腺癌、结肠癌和头颈癌的生长。该抑制剂是口服的，对小鼠没有毒性，远远超过有效剂量。该抑制剂会导致小鼠血液、组织和肿瘤中正常人体代谢物5‘-甲硫基腺苷(MTA)的增加。抑制MTAP可阻止MTA循环为S-腺苷甲硫氨酸(ADOMet)。对MTDIA产生抗药性的人FaDu头颈部癌细胞株显示出MAT2A区的特异性扩增，MAT2A区是编码癌症特异性ADOMet合成酶的催化亚单位MAT IIa的基因。本研究的目的是探讨MTDIA抗癌作用在MTAP-MAT IIa界面的生化作用机制。Mat IIa被认为是一个抗癌靶点。将建立MAT IIa过渡态结构，以促进在这一新的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状态的特异性。MTDIA作用机制的假说包括：1)MTAP抑制导致MTA的代谢积聚；2)MTA抑制MAT IIa耗尽ADMet并引起不利于肿瘤生长的下游变化；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通过与转录因子相互作用改变基因表达。MTDIA治疗引起的变化令人感兴趣，因为它们导致肿瘤生长停滞，对宿主组织具有广泛的安全边际。MAT活性的过渡态分析将为ADOMet代谢抑制剂作为抗癌靶点的设计提供蓝图。MTAP和MAT IIa是抗癌药物的新的、不断发展的目标。MTDIA的抗癌作用机制将通过其对MAT IIa/b表达的影响以及对MTA、MAT和MTDIA相互作用因子的亲和力探测来验证。过渡态类似物的低毒和独特的作用机制使其成为癌症治疗中多种药物联合治疗的候选药物。

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.