Elimusertib hydrochloride

ATR 7 nM (IC50)

盐酸伊立木赛替布能有效抑制多种人类肿瘤细胞系的增殖，中位 IC50 为 78 nM[1]。盐酸伊立木赛替布能有效抑制羟基脲诱导的 H2AX 磷酸化 (IC50: 36 nM)[1]。盐酸伊立木赛替布对 mTOR 有良好的选择性 (IC50 值比：mTOR/ATR 61)[3]。盐酸伊立木赛替布对其他相关激酶有较高的选择性，如 DNA-PK (IC50: 332 nM)、ATM (IC50: 1420 nM) 和 PI3K (IC50: 3270 nM)[3]。盐酸伊立木赛替布在体外对多种癌细胞系具有强效的抗增殖活性，25 例如 CRC 细胞系 HT-29（IC50：160 nM）和 LoVo（IC50：71 nM），以及 B 细胞淋巴瘤细胞系 SU-DHL-8（IC50：9 nM）[3]。

盐酸伊立木塞替布在多种卵巢癌和结直肠癌异种移植模型中均表现出强大的抗肿瘤疗效，并在套细胞淋巴瘤模型中引起肿瘤完全缓解[2]。盐酸伊立木塞替布（50 mg/kg；口服；每日两次；服药3天/停药4天；共11天）在小鼠ATM突变的SU-DHL-8（ATM K1964E）人类GCB-DLBCL细胞系衍生的异种移植模型中表现出强大的抗肿瘤疗效[3]。盐酸伊立木塞替布（20 mg/kg，从第 14 天开始 10 mg/kg；口服；每日一次；2 天服用/5 天停药；共 42 天）与卡铂（40 mg/kg；腹腔注射；每日一次；1 天服用/6 天停药）联合使用，在 NOD/SCID 小鼠中，铂耐药 ATM 蛋白低表达 CR5038 人类 CRC PDX 模型中产生协同抗肿瘤活性[3]。盐酸伊立木塞替布口服给药（大鼠和狗 0.6-1 mg/kg）后表现出中等口服生物利用度（大鼠 87%，狗 51%）[3]。盐酸伊立木塞替布在静脉给药（小鼠、大鼠和狗 0.3-0.5 mg/kg）后，由于血浆清除率（分别为 3.5、1.2 和 0.79 L/h/kg）而表现出终末消除半衰期（小鼠 0.17 小时、大鼠 1.3 和狗 1.0 小时）[3]。

Animal/Disease Models:Female C.B-17 SCID mice, SU-DHL-8 GCB-DLBCL xenograft model[3]
Doses: 50 mg/kg
Route of Administration: Oral administration, b.i.d., 3 days on/4 days off, for 11 days
Experimental Results: Inhibited tumor area.

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In vivo studies in CDX models [2]
The in vivo antitumor efficacy and tolerability of Elimusertib (BAY1895344) as monotherapy/combination therapy were evaluated in CDX subcutaneous or orthotopic xenograft models in mice. Monotherapy experiments were performed in GRANTA-519 (in female SCID beige mice), REC-1 (in female C.B-17 SCID mice), PC-3 (in male NMRI nude mice), LOVO, and A2780 (both in female NMRI nude mice) models treated with BAY 1895344 at 50 mg/kg [all models; twice daily, 3 days on/4 days off (3on/4off), per os/orally] or at 3, 10, or 30 mg/kg (GRANTA-519; twice daily, 3on/4off, per os/orally), ibrutinib (REC-1; 20 mg/kg, once daily, per os/orally), AZD6738 (GRANTA-519, REC-1; 50 mg/kg, once daily, per os/orally), M6620 (GRANTA-519 and REC-1; 100 mg/kg, once daily, per os/orally), or 5-FU (LOVO; 50 mg/kg, once weekly, intraperitoneally). The combination of BAY 1895344 at 10 or 20 mg/kg [once daily, 2 days on/5 days off (2on/5off), per os/orally.] or 50 mg/kg (twice daily, 3on/4off, per os/orally) and carboplatin (50 mg/kg, once weekly, intraperitoneally) was investigated in IGROV-1 tumor–bearing female nude (nu/nu) mice. The combination of 20 or 50 mg/kg BAY 1895344 (twice daily, 2on/5off, per os/orally) and EBRT (5 Gy, 7.7 minutes, once daily on days 12 and 27) was investigated in LOVO tumor–bearing female NMRI nude mice. Combination therapy experiments with 20 or 50 mg/kg BAY 1895344 (twice daily, 3on/4off, per os/orally) and 20 or 50 mg/kg olaparib (once daily, intraperitoneally) were performed in MDA-MB-436 and 22Rv1 models in female NOD/SCID and male SCID mice, respectively. Combination experiments with 20 mg/kg BAY 1895344 (twice daily, 3on/4off, per os/orally) and 100 mg/kg darolutamide (once daily, per os/orally) were performed in the hormone-dependent LAPC-4 prostate cancer model in male C.B-17 SCID mice. Castrated mice served here as a control. For a triple combination treatment, mice received EBRT (5 Gy, every 7 days twice) in addition to treatment with BAY 1895344 and darolutamide.
To elucidate the in vivo mode of action of Elimusertib (BAY1895344), ATR and H2AX phosphorylation was determined in lysed GRANTA-519 xenograft tumor samples. For the quantification of circulating ATRis, plasma samples were taken from mice and measured by LC-MS/MS.

[1]. Abstract 983: Identification of potent, highly selective and orally available ATR inhibitor BAY 1895344 with favorable PK properties and promising efficacy in monotherapy and combination in preclinical tumor models. Cancer Resea

[2]. Abstract 836: ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models. Cancer Research. July

[3]. 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

Elimusertib is an orally available ataxia telangiectasia and Rad3-related (ATR)-specific kinase inhibitor, with potential antineoplastic activity. Upon oral administration, elimusertib selectively binds to and inhibits the activity of ATR, which prevents ATR-mediated signaling. This inhibits DNA damage checkpoint activation, disrupts DNA damage repair and induces apoptosis in ATR-overexpressing tumor cells. ATR, a serine/threonine protein kinase upregulated in a variety of cancer cell types, plays a key role in DNA repair, cell cycle progression and cell survival.

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The integrity of the genome of eukaryotic cells is secured by complex signaling pathways, known as DNA damage response (DDR). Recognition of DNA damage activates DDR pathways resulting in cell cycle arrest, suppression of general translation, induction of DNA repair, cell survival or even cell death. Proteins that directly recognize aberrant DNA structures recruit and activate kinases of the DDR pathway, such as ATR (ataxia telangiectasia and Rad3-related). ATR responds to a broad spectrum of DNA damage, including double-strand breaks (DSB) and lesions derived from interference with DNA replication as well as increased replication stress (e.g. in oncogene-driven tumor cells). Therefore, inhibition of ATR kinase activity could be the basis for a novel anti-cancer therapy in tumors with increased DNA damage, deficiency in DNA damage repair or replication stress. Herein we report the identification of the potent, highly selective and orally available ATR inhibitor BAY 1895344 by a collaborative effort involving medicinal chemistry, pharmacology, DMPK and computational chemistry. The chemical structures of lead compound BAY-937 and clinical candidate BAY 1895344 as well as the main SAR trends within this novel class of naphthyridine derivatives will be disclosed for the first time. The novel lead compound BAY-937 revealed promising inhibition of ATR (IC50 = 78 nM) and high kinase selectivity in vitro. In cellular mechanistic assays BAY-937 inhibited hydroxyurea-induced H2AX phosphorylation (IC50 = 380 nM) demonstrating the anticipated mode of action. Moreover, BAY-937 was shown to inhibit proliferation of a variety of tumor cell lines with low- to sub-micromolar IC50 values. In initial xenograft studies, BAY-937 revealed moderate activity in monotherapy and in combination with cis-platin. However, BAY-937 also revealed low aqueous solubility, low bioavailability (rat) and activity in the hERG patch clamp assay. Extensive lead optimization efforts led to the identification of the novel, orally available ATR inhibitor BAY 1895344. In vitro, BAY 1895344 was shown to be a very potent and highly selective ATR inhibitor (IC50 = 7 nM), which potently inhibits proliferation of a broad spectrum of human tumor cell lines (median IC50 = 78 nM). In cellular mechanistic assays BAY 1895344 potently inhibited hydroxyurea-induced H2AX phosphorylation (IC50 = 36 nM). Moreover, BAY 1895344 revealed significantly improved aqueous solubility, bioavailability across species and no activity in the hERG patch-clamp assay. BAY 1895344 also demonstrated very promising efficacy in monotherapy in DNA damage deficient tumor models as well as combination treatment with DNA damage inducing therapies. The start of clinical investigation of BAY 1895344 is planned for early 2017. [1]

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The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective single-agent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.[2]

C20H22CLN7O

411.89

Solid powder

BAY 1895344 hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 50 mg/mL (121.39 mM; with sonication)
H2O : 50 mg/mL (121.39 mM; with sonication)

配方 1 中的溶解度: ≥ 2.08 mg/mL (5.05 mM)(饱和度未知) in 10% DMSO 40% PEG300 5% Tween-80 45% Saline (这些助溶剂从左到右依次添加，逐一添加),澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；再向上述体系中加入 50 μL Tween-80，混合均匀；然后再继续加入 450 μL 生理盐水 定容至 1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (5.05 mM)(饱和度未知) in 10% DMSO 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加),澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液 中，混合均匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (5.05 mM)(饱和度未知) in 10% DMSO 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加),澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。 以下溶解方案，请直接配制工作液。建议现用现配，在短期内尽快用完。 以下溶剂前显示的百分比是指该溶剂在您配制终溶液中的体积占比； 如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。