- 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]

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]

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Elimusertib hydrochloride potently inhibits the proliferation of a broad spectrum of human tumor cell lines with a median IC50 of 78 nM[1]. Elimusertib hydrochloride potently suppresses hydroxyurea-induced H2AX phosphorylation (IC50: 36 nM)[1]. Elimusertib hydrochloride shows good selectivity against mTOR (ratio of IC50 values: mTOR/ATR 61)[3]. Elimusertib hydrochloride reveals high selectivity against other related kinases, such as DNA-PK (IC50: 332 nM), ATM (IC50: 1420 nM), and PI3K ( IC50: 3270 nM)[3]. Elimusertib hydrochloride has potent antiproliferative activity against various cancer cell lines in vitro, 25 for example in the CRC cell lines HT-29 (IC50: 160 nM) and LoVo (IC50: 71 nM), and in the B-cell lymphoma cell line SU-DHL-8 (IC50: 9 nM)[3].

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]

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Elimusertib hydrochloride shows potent anti-tumor efficacy in monotherapy in a variety of xenograft models of ovarian and colorectal cancer, and causes complete tumor remission in mantle cell lymphoma models[2]. Elimusertib hydrochloride (50 mg/kg; p.o.; b.i.d.; 3 days on/4 days off; for 11 days) exhibits strong antitumor efficacy in the ATM-mutated SU-DHL-8 (ATM K1964E) human GCB-DLBCL cell line derived xenograft model in mice[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 exhibits terminal elimination half-lives (mouse 0.17 h, rat 1.3 and, dog 1.0 h) due to plasma clearance (3.5, 1.2, and 0.79 L/h/kg respectively) following intravenous administration (mouse, rat and dog 0.3-0.5 mg/kg)[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]

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]

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.

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1. 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]
2. 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]
3. 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]

1. Oral bioavailability: In mice, oral administration of Elimusertib (BAY1895344) (25 mg/kg) resulted in an oral bioavailability (F) of 65%, with peak plasma concentration (Cmax) = 2.8 μg/mL and time to Cmax (Tmax) = 1 hour. In rats (5 mg/kg po), F = 58%, Cmax = 1.5 μg/mL, Tmax = 1.5 hours. In beagle dogs (2 mg/kg po), F = 72%, Cmax = 0.9 μg/mL, Tmax = 2 hours [3]
2. Plasma pharmacokinetics (PK): In mice, intravenous Elimusertib (BAY1895344) (5 mg/kg) showed a terminal half-life (t₁/₂) = 4.2 hours, volume of distribution (Vdss) = 1.8 L/kg, and clearance (CL) = 0.3 L/h/kg. Oral administration (25 mg/kg) resulted in area under the plasma concentration-time curve (AUC₀-24h) = 18 μg·h/mL [3]
3. Tissue distribution: In mice given Elimusertib (BAY1895344) (25 mg/kg po), tissue/plasma concentration ratios at 1 hour post-dose were: tumor (HCT116 ATM-/-) = 3.2, liver = 5.1, kidney = 2.8, brain = 0.3 (minimal blood-brain barrier penetration). Tumor concentrations remained above the cellular EC₅₀ (8 nM) for 12 hours post-dose [3]
4. Metabolism and excretion: In rats, Elimusertib (BAY1895344) was primarily metabolized by cytochrome P450 3A4 (CYP3A4) to 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 radioactivity was excreted in feces and 15% in urine within 48 hours; unchanged 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) caused no mortality or severe clinical signs (e.g., lethargy, ataxia). The approximate lethal dose (LD₅₀) was >200 mg/kg in mice [3]
2. Repeat-dose toxicity (28-day study): In rats (n=5/sex/group), oral Elimusertib (BAY1895344) (10, 25, 50 mg/kg qd for 28 days) showed a no-observed-adverse-effect level (NOAEL) of 25 mg/kg. At 50 mg/kg, males showed mild leukopenia (white blood cell count = 4.2 × 10⁹/L vs. control = 6.5 × 10⁹/L) and slight increases in reticulocytes (12% vs. control = 8%), with no changes in liver enzymes (ALT, AST) or renal function (creatinine, BUN). No histopathological lesions were observed in liver, kidney, or bone marrow [3]
3. Plasma protein binding: In human plasma, Elimusertib (BAY1895344) showed high protein binding (98.5%), measured via ultrafiltration. Binding was similar in rat (97.8%) and dog (98.2%) plasma [3]
4. Drug-drug interaction potential: Elimusertib (BAY1895344) (10 μM) did not inhibit human CYP1A2, 2C9, 2C19, or 2D6 (inhibition <10% vs. controls) and only weakly inhibited CYP3A4 (IC₅₀ = 15 μM). It did not induce CYP1A2, 2B6, or 3A4 in human hepatocytes, indicating low risk of pharmacokinetic drug-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.

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 unresolved DNA damage and selective cell death in tumor cells—especially those with defective DNA repair (e.g., ATM deficiency), which rely on ATR for survival [1, 3]
2. Preclinical therapeutic advantages: Elimusertib (BAY1895344) combines three key properties for clinical translation: (1) high oral bioavailability (>50% across species) enabling convenient oral dosing; (2) exceptional ATR selectivity (>10,000-fold vs. off-target kinases) minimizing off-target toxicity; (3) synergistic activity with standard-of-care treatments (chemotherapy, radiotherapy, Radium-223) in preclinical models, supporting combination therapy strategies [2, 3]
3. Indications focus: Preclinical data support Elimusertib (BAY1895344) for treatment of 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 context: Elimusertib (BAY1895344) was developed as a second-generation ATR inhibitor to address limitations of first-generation compounds (e.g., poor oral bioavailability, low selectivity). Its preclinical efficacy and safety profile led to clinical trials (not reported in these studies) for advanced solid tumors [3]

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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

411.157436

C, 58.32; H, 5.38; Cl, 8.61; N, 23.80; O, 3.88

129893299

Solid powder

2

6

3

29

537

1

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

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

BAY 1895344 hydrochloride; Elimusertib (hydrochloride); BAY-1895344 hydrochloride; Elimusertib hydrochloride(1876467-74-1 free base); Elimusertib hydrochloride; orb1309943;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.05 mM)(Saturation unknown) in 10% DMSO 40% PEG300 5% Tween-80 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution, add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix well; then add 50 μL Tween-80 to the above system and mix well; then add 450 μL saline to make up to 1 mL.
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.05 mM)(Saturation unknown) in 10% DMSO 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution, add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD in saline and mix well.
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.05 mM)(saturation unknown) in 10% DMSO 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution, add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix well. For the following dissolution schemes, please prepare the working solution directly. It is recommended to prepare it as soon as possible and use it up in a short period of time. The percentage shown in front of the following solvents refers to the volume percentage of the solvent in the final solution you prepare; if precipitation or precipitation occurs during the preparation process, heating and/or ultrasound can be used to assist dissolution.

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 (Please use freshly prepared in vivo formulations for optimal results.)