AZD5305
(Synonyms: AZD5305) 目录号 : GC62310
AZD5305 is a highly selective and potent inhibitor of PARP1 with an IC50 of 3 nM in wild-type A549 lung cancer cells. AZD5305 shows no or minimal growth inhibitory effects in other cells (IC50s >10μM).
Cas No.:2589531-76-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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AZD5305 is a highly selective and potent inhibitor of PARP1 with an IC50 of 3 nM in wild-type A549 lung cancer cells. AZD5305 shows no or minimal growth inhibitory effects in other cells (IC50s >10μM).
AZD5305 is highly selective inhibitor for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species. AZD5305 reduces anti-proliferation effects on human bone marrow progenitor cells in vitro.[2]
AZD5305 is a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model.[2]
[1] Natalie Y L Ngoi, et al. Cancer J . 2021 Nov-Dec 01;27(6):521-528. [2] Johannes JW, et al.J Med Chem. 2021 Oct 14;64(19):14498-14512.
| Cas No. | 2589531-76-8 | SDF | |
| 别名 | AZD5305 | ||
| 分子式 | C22H26N6O2 | 分子量 | 406.48 |
| 溶解度 | DMSO : 41.67 mg/mL (102.51 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4601 mL | 12.3007 mL | 24.6015 mL |
| 5 mM | 0.492 mL | 2.4601 mL | 4.9203 mL |
| 10 mM | 0.246 mL | 1.2301 mL | 2.4601 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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AZD5305 More Tolerable than Earlier PARP Agents
Cancer Discov 2022 Jul 6;12(7):1602.PMID:35616497DOI:10.1158/2159-8290.CD-NB2022-0039.
Findings from the phase I/IIa trial of AZD5305, a next-generation, highly selective PARP1 inhibitor, indicate that the drug is better tolerated in patients with ovarian, HER2-negative breast, pancreatic, and prostate cancers with BRCA1/2, PALB2, and RAD51C mutations compared with first-generation PARP inhibitors. In addition, 25% of 40 evaluable patients had a partial response.
Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper
Clin Cancer Res 2022 Nov 1;28(21):4724-4736.PMID:35929986DOI:10.1158/1078-0432.CCR-22-0301.
Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination. Experimental design: AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination. Results: AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response. Conclusions: AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).
Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs
J Med Chem 2021 Oct 14;64(19):14498-14512.PMID:34570508DOI:10.1021/acs.jmedchem.1c01012.
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305
Clin Cancer Res 2023 Mar 14;29(6):1086-1101.PMID:36355054DOI:10.1158/1078-0432.CCR-22-2630.
Purpose: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. Experimental design: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. Results: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. Conclusions: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.
Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305
Front Pharmacol 2023 Jan 23;13:979873.PMID:36756144DOI:10.3389/fphar.2022.979873.
The family of poly (ADP-ribose) polymerases (PARPs) consists of 17 members, which have been demonstrated as having effects on a series of cellular processes, including DNA replication and repair. PARP inhibitors (PARPi) suppress DNA repair through "PARP trapping", thus, constitute an important treatment option for cancer nowadays. In addition, PARP inhibition and homologous recombination repair (HRR) defects are synthetically lethal, giving a promising therapeutic for homologous recombination repair deficient (HRD) tumors including BRCA mutation. However, overlapping hematologic toxicity causes PARPi to fail in combination with some first-line chemotherapies. Furthermore, recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for antitumor activity in HRD cancer models. Currently approved PARPi have shown varying levels of selectivity for the entire 17-member PARP family, hence contribute to toxicity. Together, these findings above have provided the necessity and feasibility of developing next-generation PARPi with improved selectivity for PARP1, expanding significant clinical values and wide application prospects both in monotherapy and combination with other anticancer agents. In this review, we summery the latest research of current approved PARPi, discuss the current status and future promise of next-generation PARP1-selective inhibitor AZD5305, including its reported progress up to now and anticipated impact on clinical.