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Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-06-05 , DOI: 10.1021/acs.jmedchem.0c00369
Ulrich Lücking 1 , Lars Wortmann 1 , Antje M Wengner 1 , Julien Lefranc 1 , Philip Lienau 1 , Hans Briem 1 , Gerhard Siemeister 1 , Ulf Bömer 1 , Karsten Denner 1 , Martina Schäfer 1 , Marcus Koppitz 1 , Knut Eis 1 , Florian Bartels 1 , Benjamin Bader 1 , Wilhelm Bone 1 , Dieter Moosmayer 1 , Simon J Holton 1 , Uwe Eberspächer 1 , Joanna Grudzinska-Goebel 1 , Christoph Schatz 1 , Gesa Deeg 1 , Dominik Mumberg 1 , Franz von Nussbaum 1
Affiliation  

The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA damage repair, especially in response to replication stress. Because DNA damage and replication stress are major sources of genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344. Starting from quinoline 2 with weak ATR inhibitory activity, lead optimization efforts focusing on potency, selectivity, and oral bioavailability led to the discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344, which exhibited strong monotherapy efficacy in cancer xenograft models that carry certain DNA damage repair deficiencies. Moreover, combination treatment of BAY 1895344 with certain DNA damage inducing chemotherapy resulted in synergistic antitumor activity. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965).

中文翻译:

损害合并:在临床前肿瘤模型中的单一疗法和联合治疗中发现了具有良好药代动力学特性和有希望的功效的有效,高选择性,口服ATR抑制剂BAY 1895344。

ATR激酶通过激活DNA损伤修复的基本信号通路,特别是对复制压力的响应,在DNA损伤应答中起关键作用。由于DNA损伤和复制压力是基因组不稳定的主要来源,因此选择性ATR抑制已被认为是癌症治疗中一种有希望的新方法。现在,我们报告新颖的临床ATR抑制剂BAY 1895344的鉴定和临床前评估。从喹啉2开始由于ATR抑制活性较弱,针对效价,选择性和口服生物利用度的前导优化工作导致发现了有效的,高选择性的,口服的ATR抑制剂BAY 1895344,在携带某些DNA损伤的癌症异种移植模型中显示出强大的单一疗法功效维修缺陷。此外,BAY 1895344与某些诱导DNA损伤的化学疗法联合治疗可产生协同的抗肿瘤活性。BAY 1895344目前正在对晚期实体瘤和淋巴瘤(NCT03188965)的患者进行临床研究。
更新日期:2020-07-09
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