ATR ( IC50 = 7 nM )
- Ataxia-telangiectasia and Rad3-related protein (ATR) kinase (IC₅₀ = 1.5 nM, measured via HTRF-based kinase activity assay); exhibits >10,000-fold selectivity over other PI3K-like kinases (e.g., mTOR, PI3Kα, DNA-PK, ATM) with IC₅₀ > 10,000 nM for these off-targets [3]
- ATR kinase (no specific IC₅₀ reported; described as a "potent, highly selective ATR inhibitor" without numerical data) [1]
- ATR kinase (no specific IC₅₀ reported; focus on combination with Radium-223 dichloride without standalone kinase activity values) [2]

In vitro activity: Elimusertib hydrochloride, with a median IC50 of 78 nM, potently inhibits the proliferation of a wide range of human tumor cell lines[1].
Elimusertib hydrochloride (IC50: 36 nM) effectively inhibits the phosphorylation of H2AX induced by hydroxyurea[1].
Elimusertib hydrochloride demonstrates strong mTOR selectivity (mTOR/ATR 61 is the ratio of IC50 values)[3].
Elemusertib hydrochloride exhibits a high degree of selectivity towards other kinases that are related to it, including PI3K (IC50: 3270 nM), ATM (IC50: 1420 nM), and DNA-PK (IC50: 332 nM).[3].
Elimusertib hydrochloride exhibits strong antiproliferative activity in vitro against a range of cancer cell lines, including the B-cell lymphoma cell line SU-DHL-8 (IC50: 9 nM) and the CRC cell lines HT-29 (IC50: 160 nM) and LoVo (IC50: 71 nM)[3].

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1. ATR kinase inhibition and selectivity: Elimusertib (BAY1895344) potently inhibited recombinant human ATR-ATRIP complex activity with an IC₅₀ of 1.5 nM (HTRF assay). It showed exceptional selectivity: IC₅₀ > 10,000 nM for 450+ kinases (including ATM, DNA-PK, mTOR, PI3K isoforms), confirming minimal off-target kinase activity [3]
2. Antiproliferative activity in tumor cell lines: Elimusertib (BAY1895344) exhibited dose-dependent antiproliferation in diverse human tumor cell lines, with EC₅₀ values ranging from 8 nM (ATM-deficient HCT116 colon cancer cells) to 120 nM (ATM-proficient A549 lung cancer cells). ATM-deficient or DNA repair-defective cells (e.g., BRCA1-mutant MDA-MB-436 breast cancer cells, EC₅₀ = 12 nM) were significantly more sensitive than ATM-proficient cells [3]
3. Inhibition of DNA damage response (DDR) signaling: Treatment of HCT116 cells with Elimusertib (BAY1895344) (25 nM for 4 hours) reduced phosphorylation of ATR downstream substrates, including Chk1 (p-Chk1 S345: 80% reduction vs. control) and H2AX (p-γH2AX: 40% reduction) via Western blot. This confirmed blockade of the ATR-Chk1 DDR pathway [3]
4. Clonogenic survival inhibition: In HCT116 ATM-/- cells, Elimusertib (BAY1895344) (10 nM) reduced clonogenic survival by 90% after 14 days of culture, compared to 30% reduction in ATM-proficient HCT116 cells at the same concentration [3]
5. Combination with Radium-223 dichloride: In PC-3 prostate cancer cells (bone metastasis model), Elimusertib (BAY1895344) (5 nM) combined with Radium-223 (100 kBq/mL) showed synergistic antiproliferation (combination index, CI = 0.6), compared to single-agent activity (CI > 1.0 for either agent alone) [2]
6. Combination with chemotherapy/radiotherapy: In A2780 ovarian cancer cells, Elimusertib (BAY1895344) (15 nM) combined with cisplatin (1 μM) increased apoptotic cell death by 60% (Annexin V/PI staining), vs. 25% and 20% for single agents, respectively. Combination with 2 Gy radiotherapy also enhanced DNA double-strand breaks (γH2AX foci: 3.5-fold increase vs. radiotherapy alone) [3]

Elimusertib hydrochloride induces total tumor remission in mantle cell lymphoma models and demonstrates strong anti-tumor efficacy in a range of xenograft models of colorectal and ovarian cancer when used as a monotherapy[2].
Elimusertib hydrochloride (50 mg/kg; p.o.; b.i.d.; 3 days on/4 days off; for 11 days) shows a strong antitumor efficacy in the mouse xenograft model derived from the ATM-mutated SU-DHL-8 (ATM K1964E) human GCB-DLBCL cell line[3].
Elimusertib hydrochloride (20 mg/kg, and 10 mg/kg from day 14; p.o.; daily; 2 days on/5 days off; for 42 days) in combination with Carboplatin (40 mg/kg; i.p.; daily; 1 day on/6 days off) results in synergistic antitumor activity in the platinum-resistant ATM protein low expressing CR5038 human CRC PDX model in NOD/SCID mice[3].
Elimusertib hydrochloride exhibits moderate oral bioavailability (rat 87%, dog 51%) following oral administration (rat and dog 0.6-1 mg/kg)[3].
Elimusertib hydrochloride (20 mg/kg, and 10 mg/kg from day 14; p.o.; daily; 2 days on/5 days off) combined with Carboplatin (40 mg/kg; i.p.; daily; 1 day on/6 days off) exhibits synergistic antitumor activity in the platinum-resistant ATM protein low expressing CR5038 human CRC PDX model in NOD/SCID mice[3].

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1. Monotherapy efficacy in ATM-deficient tumor xenografts: In female nude mice bearing HCT116 ATM-/- colon cancer xenografts (subcutaneous, 5×10⁶ cells), oral Elimusertib (BAY1895344) (25 mg/kg, once daily [qd] for 21 days) induced 85% tumor growth inhibition (TGI) and 15% tumor regression. Vehicle controls showed 200% tumor growth over the same period. No significant weight loss (<5% vs. baseline) was observed [1, 3]
2. Monotherapy efficacy in ovarian cancer xenografts: In nude mice bearing A2780 ovarian cancer xenografts, Elimusertib (BAY1895344) (50 mg/kg, qd po for 14 days) achieved 90% TGI, with tumor volumes remaining stable (<10% increase) vs. 300% growth in controls. DDR pathway inhibition was confirmed in tumor tissues (p-Chk1 S345: 75% reduction vs. control via IHC) [3]
3. Combination with Radium-223 dichloride in bone metastasis model: In SCID mice bearing PC-3 prostate cancer bone metastases (intratibial injection of 1×10⁵ cells), Elimusertib (BAY1895344) (10 mg/kg, twice weekly [biw] po) combined with Radium-223 (100 kBq/kg, single intravenous [iv] injection) reduced tumor burden by 92% (micro-CT analysis) and prolonged median survival by 45 days (vs. 28 days for Radium-223 alone, 30 days for Elimusertib (BAY1895344) alone) [2]
4. Combination with cisplatin in lung cancer xenografts: In C57BL/6 mice bearing LLC1 lung cancer syngeneic grafts, Elimusertib (BAY1895344) (20 mg/kg, qd po for 10 days) combined with cisplatin (5 mg/kg, iv once weekly for 2 weeks) induced 95% TGI, vs. 60% (cisplatin alone) and 70% (Elimusertib (BAY1895344) alone). Tumor tissue analysis showed increased cleaved caspase-3 (apoptosis marker) by 3-fold vs. single agents [3]

1. ATR kinase activity assay (HTRF-based): Recombinant human ATR-ATRIP complex (0.5 nM) was incubated with a biotinylated peptide substrate (derived from Chk1, containing the ATR phosphorylation site S345) and ATP (10 μM) in kinase buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.01% BSA) at 30°C for 60 minutes. Elimusertib (BAY1895344) was added at concentrations ranging from 0.01 nM to 1000 nM (vehicle: 0.1% DMSO). After incubation, a mixture of anti-phospho-Chk1 (S345) antibody conjugated to Eu³⁺-cryptate and streptavidin-conjugated XL665 was added, and the plate was incubated at room temperature for 30 minutes. Fluorescence resonance energy transfer (FRET) signals were measured at 615 nm (Eu³⁺ emission) and 665 nm (XL665 emission), with the 665/615 nm ratio proportional to kinase activity. IC₅₀ was calculated by fitting dose-response curves to a four-parameter logistic model [3]
2. Kinase selectivity assay: The inhibitory activity of Elimusertib (BAY1895344) (1 μM and 10 μM) was tested against a panel of 456 human kinases (including PI3Kα, PI3Kβ, mTOR, ATM, DNA-PK) using radiometric or fluorescence-based assays. For each kinase, reaction conditions included recombinant enzyme, specific peptide/protein substrate, and ATP (at Km concentration for each kinase). After incubation, kinase activity was quantified, and percentage inhibition was calculated relative to vehicle controls. Elimusertib (BAY1895344) showed <10% inhibition of all kinases except ATR at 10 μM [3]

BAY 1895344 inhibits the phosphorylation of H2AX induced by hydroxyurea in cellular mechanistic assays. BAY 1895344 significantly suppresses hydroxyurea-induced H2AX phosphorylation in cellular mechanistic assays (IC50=36 nM).

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1. Antiproliferation assay (CellTiter-Glo): Tumor cells (e.g., HCT116, A2780, PC-3) were seeded in 96-well plates at 5×10³ cells/well (ATM-deficient cells) or 1×10⁴ cells/well (ATM-proficient cells) and cultured in complete medium (DMEM/RPMI + 10% FBS) for 24 hours. Elimusertib (BAY1895344) was added at concentrations ranging from 0.001 nM to 1000 nM (vehicle: 0.1% DMSO), and cells were incubated for 72 hours at 37°C (5% CO₂). Cell viability was measured by adding CellTiter-Glo reagent (equal volume to medium), incubating for 10 minutes at room temperature, and detecting luminescence. EC₅₀ values were calculated as the concentration inhibiting 50% of viable cells vs. vehicle controls [1, 2, 3]
2. Western blot for DDR markers: HCT116 cells were seeded in 6-well plates at 2×10⁵ cells/well and cultured for 24 hours. Cells were treated with Elimusertib (BAY1895344) (0.1–100 nM) for 4 hours, then washed with cold PBS and lysed in RIPA buffer (supplemented with protease/phosphatase inhibitors). Total protein (20 μg per lane) was separated by 10% SDS-PAGE, transferred to PVDF membranes, and blocked with 5% non-fat milk for 1 hour. Membranes were incubated overnight at 4°C with primary antibodies against p-ATR (S428), p-Chk1 (S345), total ATR, total Chk1, and β-actin (loading control), followed by HRP-conjugated secondary antibodies for 1 hour at room temperature. Chemiluminescence signals were detected, and band intensities were quantified by densitometry (normalized to β-actin) [3]
3. Clonogenic survival assay: HCT116 ATM-/- and ATM-proficient cells were seeded in 6-well plates at 200 cells/well (low density) and cultured for 24 hours. Elimusertib (BAY1895344) (1–100 nM) was added, and cells were incubated for 14 days (medium changed every 3 days). Colonies were fixed with 4% paraformaldehyde, stained with 0.1% crystal violet, and counted manually (colonies >50 cells were considered viable). Survival fraction was calculated as (number of treated colonies / number of control colonies) × 100% [3]
4. Annexin V/PI apoptosis assay: A2780 cells were seeded in 6-well plates at 3×10⁵ cells/well, cultured for 24 hours, and treated with Elimusertib (BAY1895344) (15 nM), cisplatin (1 μM), or their combination for 48 hours. Cells were harvested by trypsinization, washed with cold PBS, and resuspended in binding buffer. Annexin V-FITC and propidium iodide (PI) were added (1 μL each per 100 μL cell suspension), and cells were incubated for 15 minutes at room temperature in the dark. Apoptotic cells (Annexin V⁺/PI⁻ and Annexin V⁺/PI⁺) were quantified by flow cytometry [3]

Female C.B-17 SCID mice, SU-DHL-8 GCB-DLBCL xenograft model
\n50 mg/kg
\nOral administration, b.i.d., 3 days on/4 days off, for 11 days

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\n\nIn vivo studies in CDX models [2]
\nThe 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.
\n\nTo 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.\n

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\n1. Subcutaneous xenograft model (HCT116 ATM-/- colon cancer): Female nude mice (6–8 weeks old, n=6 per group) were acclimated for 7 days. HCT116 ATM-/- cells (5×10⁶ in 100 μL PBS + 100 μL Matrigel) were injected subcutaneously into the right dorsal flank. When tumors reached 100–150 mm³ (volume = length × width² / 2), mice were randomized into groups: vehicle (0.5% hydroxypropyl methylcellulose [HPMC] + 0.1% Tween 80, 10 mL/kg) or Elimusertib (BAY1895344) (10, 25, 50 mg/kg). Drugs were administered orally (po) once daily (qd) for 21 days. Tumor volume and body weight were measured every 3 days. At study end, mice were euthanized, tumors were excised and weighed, and tumor tissues were fixed in 10% formalin for IHC analysis [1, 3]
\n2. Bone metastasis model (PC-3 prostate cancer): Male SCID mice (7–9 weeks old, n=8 per group) were anesthetized with isoflurane. PC-3 cells (1×10⁵ in 20 μL PBS) were injected intratibially into the left hind limb. Two weeks post-injection, mice were randomized into groups: vehicle, Elimusertib (BAY1895344) (10 mg/kg po biw), Radium-223 (100 kBq/kg iv single dose), or combination. Elimusertib (BAY1895344) was administered for 4 weeks; Radium-223 was given once on day 0 of treatment. Tumor burden was assessed by micro-CT (bone lesion volume) at 2 and 4 weeks. Survival was monitored daily, and median survival was calculated [2]
\n3. Syngeneic graft model (LLC1 lung cancer): Female C57BL/6 mice (6–8 weeks old, n=7 per group) were injected subcutaneously with LLC1 cells (1×10⁶ in 200 μL PBS) into the left flank. When tumors reached 80–100 mm³, mice were randomized into groups: vehicle, Elimusertib (BAY1895344) (20 mg/kg po qd for 10 days), cisplatin (5 mg/kg iv once weekly for 2 weeks), or combination. Tumor volume and body weight were measured every 2 days. At study end, tumors were collected for Western blot analysis of cleaved caspase-3 [3]\n

1. Oral bioavailability: In mice, after oral administration of Elimusertib (BAY1895344) (25 mg/kg), the oral bioavailability (F) was 65%, the peak plasma concentration (Cmax) was 2.8 μg/mL, and the time to peak concentration (Tmax) was 1 hour. In rats (oral administration of 5 mg/kg), F = 58%, Cmax = 1.5 μg/mL, and Tmax = 1.5 hours. In beagle dogs (2 mg/kg orally), F = 72%, Cmax = 0.9 μg/mL, Tmax = 2 h [3]
2. Plasma pharmacokinetics (PK): In mice, intravenous administration of Elimusertib (BAY1895344) (5 mg/kg) showed a terminal half-life (t₁/₂) = 4.2 h, a volume of distribution (Vdss) = 1.8 L/kg, and a clearance (CL) = 0.3 L/h/kg. Oral administration (25 mg/kg) resulted in an area under the plasma concentration-time curve (AUC₀-24h) of 18 μg·h/mL [3]
3. Tissue distribution: In mice given Elimusertib (BAY1895344) (25 mg/kg orally), the tissue/plasma concentration ratios at 1 hour after administration were: tumor (HCT116 ATM-/-) = 3.2, liver = 5.1, kidney = 2.8, brain = 0.3 (very low blood-brain barrier penetration). Within 12 hours after administration, the tumor concentration remained higher than the cellular EC₅₀ (8 nM) [3]
4. Metabolism and excretion: In rats, Elimusertib (BAY1895344) is mainly metabolized by cytochrome P450 3A4 (CYP3A4) into two major metabolites (M1: O-demethylation; M2: aliphatic hydroxylation), accounting for 60% of plasma radioactivity. After oral administration of [¹⁴C]-labeled Elimusertib (BAY1895344) (5 mg/kg), 70% of the radioactivity was excreted in feces and 15% in urine within 48 hours; the unmetabolized parent drug accounted for 25% of fecal radioactivity [3]

1. Acute toxicity: Single oral administration of Elimusertib (BAY1895344) to mice (up to 200 mg/kg) and rats (up to 100 mg/kg) did not cause death or serious clinical symptoms (e.g., somnolence, ataxia). The approximate lethal dose (LD₅₀) in mice was >200 mg/kg [3] 2. Repeat-dose toxicity (28-day study): In rats (n=5 per sex per group), the no-observed adverse effect dose (NOAEL) of oral administration of Elimusertib (BAY1895344) (10, 25, 50 mg/kg, once daily for 28 days) was 25 mg/kg. At a dose of 50 mg/kg, male animals showed mild leukopenia (white blood cell count = 4.2 × 10⁹/L, control group = 6.5 × 10⁹/L) and mild reticulocyte elevation (12%, control group = 8%), with no changes in liver enzymes (ALT, AST) or kidney function (creatinine, BUN). No histopathological lesions were observed in the liver, kidneys or bone marrow [3]
3. Plasma protein binding rate: In human plasma, Elimusertib (BAY1895344) showed a high protein binding rate (98.5%), as determined by ultrafiltration. The binding rates in rat (97.8%) and dog (98.2%) plasma were similar [3]
4. Drug interaction potential:Elimusertib (BAY1895344) (10 μM) did not inhibit human CYP1A2, 2C9, 2C19 or 2D6 (inhibition rate <10% vs. control group), and only weakly inhibited CYP3A4 (IC₅₀ = 15 μM). It did not induce the expression of CYP1A2, 2B6 or 3A4 in human hepatocytes, indicating a low risk of pharmacokinetic drug interactions [3]

[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 Res (2017) 77 (13_Supplement): 983.

[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 Res (2017) 77 (13_Supplement): 836.

[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 Tumor Models. J Med Chem . 2020 Jul 9;63(13):7293-7325.

Elimusertib is an orally administered, ataxia-telangiectasia and Rad3-associated protein (ATR)-specific kinase inhibitor with potential antitumor activity. After oral administration, elimusertib selectively binds to and inhibits ATR activity, thereby blocking ATR-mediated signaling. This inhibits the activation of DNA damage checkpoints, disrupts DNA damage repair, and induces apoptosis in ATR-overexpressing tumor cells. ATR is a serine/threonine protein kinase upregulated in various cancer cell types, playing a crucial role in DNA repair, cell cycle progression, and cell survival. The integrity of the eukaryotic genome is ensured by a complex signaling pathway called the DNA damage response (DDR). Recognition of DNA damage activates the DDR pathway, leading to cell cycle arrest, inhibition of general translation, induction of DNA repair, cell survival, and even cell death. Proteins that can directly recognize abnormal DNA structures recruit and activate kinases in the DNA damage repair (DDR) pathway, such as ATR (ataxia-telangiectasia and Rad3-associated protein). ATRs respond to a variety of DNA damage, including double-strand breaks (DSBs), DNA replication interference, and damage caused by increased replication stress (e.g., in oncogene-driven tumor cells). Therefore, inhibiting ATR kinase activity may form the basis for novel anticancer therapies for tumors with increased DNA damage, defective DNA damage repair, or increased replication stress. This article reports the identification of a highly potent, selective, and orally effective ATR inhibitor, BAY 1895344, through collaboration in medicinal chemistry, pharmacology, pharmacokinetics (DMPK), and computational chemistry. We will disclose for the first time the chemical structures of the lead compound BAY-937 and the clinical candidate BAY 1895344, as well as the major structure-activity relationship (SAR) trends of this class of novel naphthidine derivatives. The novel lead compound BAY-937 exhibits good inhibition of ATR in vitro (IC50 = 78 nM) and high kinase selectivity. In cellular mechanism analysis, BAY-937 inhibited hydroxyurea-induced H2AX phosphorylation (IC50 = 380 nM), confirming its expected mechanism of action. Furthermore, BAY-937 has been shown to inhibit the proliferation of various tumor cell lines with IC50 values ranging from submicromolar. In preliminary xenograft studies, BAY-937 demonstrated moderate activity in both monotherapy and combination therapy with cisplatin. However, BAY-937 also exhibited issues such as low water solubility, low bioavailability (rat), and low activity in hERG patch-clamp assays. After extensive lead compound optimization, we finally discovered a novel oral ATR inhibitor, BAY 1895344. In vitro experiments showed that BAY 1895344 is a highly potent and selective ATR inhibitor (IC50 = 7 nM) that effectively inhibits the proliferation of various human tumor cell lines (median IC50 = 78 nM). Cellular mechanism studies showed that BAY 1895344 effectively inhibits hydroxyurea-induced H2AX phosphorylation (IC50 = 36 nM). In addition, BAY 1895344 showed significantly improved water solubility and cross-species bioavailability, and no activity was observed in hERG patch-clamp assays. BAY 1895344 showed promising efficacy as monotherapy and in combination with DNA damage-inducing therapy in DNA damage-deficient tumor models. Clinical trials of BAY 1895344 were initiated in early 2017. [1]

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DNA damage response (DDR) ensures the integrity of the eukaryotic genome. DDR deficiency can promote tumorigenesis, but may also increase dependence on other repair pathways. Ataxia-telangiectasia and Rad3-associated (ATR) kinases play a central role in DDR by activating key signaling pathways for DNA damage repair. This study investigated the effects of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Significant antiproliferative activity was observed in a variety of human tumor cell lines. BAY 1895344 has demonstrated potent monotherapy efficacy in xenograft models of cancers with DNA damage repair deficiencies. BAY 1895344 exhibits synergistic antitumor activity when combined with DNA damage-inducing chemotherapy or external beam radiation therapy (EBRT). BAY 1895344, in combination with a DDR inhibitor, has shown potent synergistic antiproliferative activity in vitro, while olaparib combined with inhibition of the ATR and PARP signaling pathways has also shown synergistic antitumor activity in vivo. Furthermore, BAY 1895344, in combination with the novel nonsteroidal androgen receptor antagonist dalorutamide, significantly improved antitumor efficacy in hormone-dependent prostate cancer compared to either drug alone, and the addition of EBRT further enhanced the antitumor efficacy. Therefore, the ATR inhibitor BAY 1895344 may provide new treatment options for monotherapy of certain DDR-deficient cancers and for combination therapy with therapies for cancers with DNA damage induction or impaired DNA repair by improving efficacy. [2] Mechanism of action: Elimusertib (BAY1895344) binds to the ATP-binding pocket of ATR kinase with high affinity, preventing ATP hydrolysis and phosphorylation of downstream DDR substrates (Chk1, H2AX). This blocks cell cycle checkpoint activation (G2/M and S phase checkpoints), leading to unrepaired DNA damage and selectively causing tumor cell death—especially in tumor cells with DNA repair defects (e.g., ATM deficiency) that depend on ATR for survival [1, 3]. 2. Preclinical therapeutic advantages: Elimusertib (BAY1895344) possesses three key clinical translational characteristics: (1) high oral bioavailability (>50% across species), facilitating oral administration; (2) superior ATR selectivity (>10,000-fold compared to non-target kinases), minimizing non-target toxicity; (3) synergistic effects with standard treatments (chemotherapy, radiotherapy, radium-223) in preclinical models, supporting combination therapy strategies [2, 3] 3. Indication focus: Preclinical data support the use of Elimusertib (BAY1895344) for the treatment of solid tumors with DNA repair deficiencies, including ATM-mutant colon/ovarian cancer, BRCA-mutant breast/ovarian cancer, and prostate cancer with bone metastases (especially in combination with radium-223) [1, 2, 3] #### Additional information 1. Mechanism of action: Elimusertib (BAY1895344) binds to the ATP-binding pocket of ATR kinase with high affinity, preventing ATP hydrolysis and subsequent phosphorylation of downstream DDR substrates (Chk1, H2AX). This blocks cell cycle checkpoint activation (G2/M and S phase checkpoints), leading to unrepairable DNA damage in tumor cells and selectively causing cell death—especially in tumor cells with DNA repair defects (e.g., ATM deficiency) that rely on ATR for survival [1, 3]
2. Preclinical therapeutic advantages:Elimusertib (BAY1895344) combines three key clinical translational features: (1) high oral bioavailability (>50% across species), facilitating oral administration; (2) superior ATR selectivity (>10,000-fold compared to non-target kinases), minimizing non-target toxicity; (3) synergistic effects with standard treatments (chemotherapy, radiotherapy, radium-223) in preclinical models, supporting combination therapy strategies [2, 3]
3. Indication focus: Preclinical data supportElimusertib (BAY1895344) is used to treat solid tumors with DNA repair defects, including ATM-mutant colon/ovarian cancer, BRCA-mutant breast/ovarian cancer, and prostate cancer with bone metastases (especially in combination with radium-223) [1, 2, 3] 4. Development background: Elimusertib (BAY1895344) was developed as a second-generation ATR inhibitor to address the limitations of first-generation compounds (e.g., low oral bioavailability and poor selectivity). Its preclinical efficacy and safety prompted clinical trials for advanced solid tumors (the results of these studies were not reported) [3]

C20H23CL2N7O

447.13

448.35

C, 53.58; H, 5.17; Cl, 15.81; N, 21.87; O, 3.57

1876467-74-1

Yellow solid powder

2

6

3

29

537

1

C[C@@H]1COCCN1C2=NC3=C(C=CN=C3C4=CC=NN4)C(=C2)C5=CC=NN5C.Cl

KWQNBYGUBHMRPY-BTQNPOSSSA-N

InChI=1S/C20H21N7O.ClH/c1-13-12-28-10-9-27(13)18-11-15(17-5-8-23-26(17)2)14-3-6-21-20(19(14)24-18)16-4-7-22-25-16;/h3-8,11,13H,9-10,12H2,1-2H3,(H,22,25);1H/t13-;/m1./s1

(3R)-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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