Methylthioadenosine Phosphorylase and AdoMet Synthetase in Cancer

癌症中的甲硫腺苷磷酸化酶和 AdoMet 合成酶

• 批准号: 9052718
• 负责人: Vern L. Schramm
• 金额: $ 29.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052718
• 关键词: Adverse effects; Affinity; Animal Model; Antibodies; Antineoplastic Agents; Back; Biochemical; Biology; Blood; Breast; Cancer Cell Growth; Cancer cell line; Catalysis; Catalytic Domain; Cells; Chemicals; Chromatin; Colon; Complement; Complex; Dose; Drug Combinations; Enzymes; Epitopes; Event; Exhibits; Extrahepatic; Fostering; Gene Expression; Generations; Genes; Goals; Growth; Head and Neck Cancer; Health; Human; Human Genome; Isoenzymes; Isotopes; Kinetics; Knowledge; Ligands; Ligase; Liver; Lung; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolism; Modification; Mus; Natural regeneration; Normal Cell; Pathway interactions; Phenotype; Phosphorylases; Polyamines; Post-Translational Protein Processing; Property; Prostate; Protein Isoforms; Proteins; Recycling; Regulation; Reporting; Research; Resistance; S-Adenosylmethionine; Safety; Specificity; Spermine; Structure; Sulfur; System; Testing; Tissues; Toxic effect; Tumor Tissue; Work; Xenograft procedure; analog; anticancer activity; cancer therapy; design; dimer; feeding; genome analysis; inhibitor/antagonist; innovation; interest; meetings; novel; novel anticancer drug; overexpression; prevent; protein expression; protein protein interaction; quantum; theories; tool; transcription factor; tumor; tumor growth

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.

描述（由申请人提供）：癌症治疗的目标是阻止肿瘤生长，同时对正常细胞影响最小。过渡态理论被用来设计针对特定酶的强大抑制剂。人 5'-甲硫腺苷磷酸化酶 (MTAP) 的过渡态类似物 (MTDIA) 可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，并且对远超过有效剂量的小鼠没有毒性。该抑制剂会导致小鼠血液、组织和肿瘤中正常人类代谢物 5'-甲硫腺苷 (MTA) 增加。 MTAP 的抑制可防止 MTA 再循环为 S-腺苷甲硫氨酸 (AdoMet)。对 MTDIA 具有抗性的人 FaDu 头颈癌细胞系表现出 MAT2A 区域的特异性扩增，该区域是编码 MAT IIa 的基因，而 MAT IIa 是癌症特异性 AdoMet 合成酶的催化亚基。本研究的目标是研究 MTDIA 在 MTAP-MAT IIa 界面上的抗癌作用的生化机制。 MAT IIa 被认为是一种抗癌靶点。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。 MTDIA 作用机制的假设包括： 1) MTAP 抑制导致 MTA 代谢积累； 2) MTA 抑制 MAT IIa 消耗 AdoMet 并引起下游变化，不利于肿瘤生长； 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，其调节亚单位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来改变基因表达。 MTDIA 治疗引起的变化令人感兴趣，因为它们会导致肿瘤生长停滞，对宿主组织具有很大的安全性。 MAT 活性的过渡态分析将为 AdoMet 代谢作为抗癌靶点的抑制剂设计提供蓝图。 MTAP 和 MAT IIa 是抗癌药物不断发展的新靶点。 MTDIA 的抗癌作用机制将通过其对 MAT IIa/b 表达的影响以及 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组合的有前途的候选者。