Discovery of ERK5 inhibitors for biomarker-driven clinical evaluation in cancer

发现 ERK5 抑制剂用于癌症生物标志物驱动的临床评估

• 批准号: MR/K007580/1
• 负责人: Herbie Newell
• 金额: $ 106.06万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK007580%2F1
• 关键词: Discovery; ERK5; inhibitors; biomarker; driven

Cancer is now the commonest cause of death from disease in the UK, and increasingly in all developed countries. In the UK, prostate cancer is the most common malignancy in males, breast cancer the most common in females and, worldwide, liver cancer is the 3rd most common tumour type. Therapeutic options for the common cancers remain limited, and only drug therapy is of proven benefit for the management of metastatic disease, the primary cause of death in cancer patients. Although the range and activity of drugs available for cancer treatment are improving, over 150,000 patients still die of the disease in the UK each year. Hence there remains a substantial unmet clinical need, and ERK5 is an exciting new drug target in multiple tumours including prostate, breast and liver cancer.Selective and potent inhibitors of the signalling enzyme ERK5 will be developed and a clinical trial candidate and a back-up compound identified during the 2 year MRC DPFS award. Subsequently, the compound(s) will be evaluated in patients with cancer and the clinical development pathway for new cancer medicines is well-defined. Importantly, ERK5 inhibitors are representative of the new generation of targeted cancer drugs and hence a comprehensive portfolio of tests or biomarkers is essential for the optimal pre-clinical and clinical development of drug candidates, and their eventual use as stratified medicines - i.e. making sure that the right patient gets the right drug at the right time. These biomarkers will be developed alongside the drug candidate using invasive (biopsy) and non-invasive (imaging) technologies.The research output, a new drug in a new class, will provide an exciting new treatment option for patients with cancer. Furthermore, the co-development of biomarkers will allow the treatment to be directed towards those patients who are most likely to benefit, and allow the early evaluation of the therapeutic potential of ERK5 inhibitors.

癌症现在是英国最常见的疾病死亡原因，在所有发达国家也越来越多。在英国，前列腺癌是男性中最常见的恶性肿瘤，乳腺癌是女性中最常见的恶性肿瘤，在全球范围内，肝癌是第三大常见肿瘤类型。常见癌症的治疗选择仍然有限，只有药物治疗被证明对转移性疾病的管理有益，转移性疾病是癌症患者死亡的主要原因。尽管可用于癌症治疗的药物的范围和活性正在改善，但英国每年仍有超过15万名患者死于这种疾病。因此，仍然有大量的未满足的临床需求，ERK 5是一个令人兴奋的新药物靶点，在多种肿瘤，包括前列腺癌，乳腺癌和肝癌。选择性和有效的抑制剂的信号酶ERK 5将开发和临床试验候选人和备份化合物确定在2年MRC DPFS奖。随后，将在癌症患者中评估化合物，并明确定义新癌症药物的临床开发途径。重要的是，ERK 5抑制剂是新一代靶向癌症药物的代表，因此全面的测试或生物标志物组合对于候选药物的最佳临床前和临床开发以及最终用作分层药物至关重要-即确保正确的患者在正确的时间获得正确的药物。这些生物标志物将与候选药物一起使用侵入性（活检）和非侵入性（成像）技术进行开发。研究成果是一种新的药物，将为癌症患者提供令人兴奋的新治疗选择。此外，生物标志物的共同开发将使治疗能够针对那些最有可能受益的患者，并允许早期评估ERK 5抑制剂的治疗潜力。

项目成果

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

• DOI: 10.1021/acs.jmedchem.1c01756
• 发表时间: 2022-05-12
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Miller, Duncan C.;Reuillon, Tristan;Molyneux, Lauren;Blackburn, Timothy;Cook, Simon J.;Edwards, Noel;Endicott, Jane A.;Golding, Bernard T.;Griffin, Roger J.;Hardcastle, Ian;Harnor, Suzannah J.;Heptinstall, Amy;Lochhead, Pamela;Martin, Mathew P.;Martin, Nick C.;Myers, Stephanie;Newell, David R.;Noble, Richard A.;Phillips, Nicole;Rigoreau, Laurent;Thomas, Huw;Tucker, Julie A.;Wang, Lan-Zhen;Waring, Michael J.;Wong, Ai-Ching;Wedge, Stephen R.;Noble, Martin E. M.;Cano, Celine
• 通讯作者: Cano, Celine

Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation.

• DOI: 10.1080/15384101.2015.1120915
• 发表时间: 2016
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Lochhead PA;Clark J;Wang LZ;Gilmour L;Squires M;Gilley R;Foxton C;Newell DR;Wedge SR;Cook SJ
• 通讯作者: Cook SJ

Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy.

• DOI: 10.1021/acs.jmedchem.3c00072
• 发表时间: 2023-04-13
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Miller, Duncan C.;Harnor, Suzannah J.;Martin, Mathew P.;Noble, Richard A.;Wedge, Stephen R.;Cano, Celine
• 通讯作者: Cano, Celine