H3B-6545
目录号 : GC32406
H3B-6545是一种口服有效的选择性雌激素受体共价拮抗剂(SERCA)。
Cas No.:2052130-80-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
H3B-6545 is an oral, selective estrogen receptor covalent antagonist (SERCA).
H3B-6545 is a highly selective small molecule that potently antagonizes wild-type and mutant ERα in biochemical and cell based assays. In vitro comparisons with standard of care and other experimental agents confirm increased cell potency of H3B-6545 under continuous as well as washout treatment conditions[1]. H3B-6545, a member of a novel class of ERα antagonists refer to as selective ER covalent antagonist (SERCA), which inactivates both wild-type and mutant ERα by targeting C530 and enforcing a unique antagonist conformation. H3B-6545 is a first-in-class selective ER covalent antagonist (SERCA). H3B-6545 inhibits ERαWT activity and growth of ERαWT -positive breast cancer lines. H3B-6545 potently inhibits ERαWT activity and suppresses proliferation of ERαWT -positive breast cancer lines. With GI50s of 0.3-0.4, 1.0, 0.5, 5.2, and 0.2 nM for MCF7, HCC1428, BT483, T47D and CAMA-1 cell lines[1].
In vivo, once daily oral dosing of H3B-6545 shows potent activity and superior efficacy to fulvestrant in the MCF-7 xenograft model with maximal antitumor activity at doses >10x below the maximum tolerated dose in mice. In addition, H3B-6545 shows superior antitumor activity to Tamoxifen and Fulvestrant in patient derived xenograft models of estrogen receptor positive breast cancer including models carrying ERα mutations in rat and monkeys, H3B-6545 is well tolerated across a broad dose range and at exposures that significantly exceed those required for efficacy in mouse xenograft models[1].
[1]. Peter G. Smith, et al. Abstract DDT01-04: Discovery and development of H3B-6545: A novel, oral, selective estrogen receptor covalent antagonist (SERCA) for the treatment of breast cancer.AACR Annual Meeting 2017; April 1-5. [2]. Manav Korpal, et al. Development of a First-in-Class Oral Selective ER Covalent Antagonist (SERCA) for the Treatment of ERαWT and ERαMUT Breast Cancer.
| Cas No. | 2052130-80-8 | SDF | |
| Canonical SMILES | O=C(N(C)C)/C=C/CNCCOC1=NC=C(/C(C2=CC3=C(NN=C3F)C=C2)=C(C4=CC=CC=C4)/CC(F)(F)F)C=C1 | ||
| 分子式 | C30H29F4N5O2 | 分子量 | 567.58 |
| 溶解度 | Soluble in DMSO | 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 | 1.7619 mL | 8.8093 mL | 17.6187 mL |
| 5 mM | 0.3524 mL | 1.7619 mL | 3.5237 mL |
| 10 mM | 0.1762 mL | 0.8809 mL | 1.7619 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer
Mol Cancer Ther 2022 Jun 1;21(6):890-902.PMID:35642432DOI:10.1158/1535-7163.MCT-21-0378.
Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy-resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.
Nonclinical pharmacokinetics and in vitro metabolism of H3B-6545, a novel selective ERα covalent antagonist (SERCA)
Cancer Chemother Pharmacol 2019 Jan;83(1):151-160.PMID:30386887DOI:10.1007/s00280-018-3716-3.
Purpose: H3B-6545, a novel selective estrogen receptor (ER)α covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα, is in clinical development for the treatment of metastatic breast cancer. Preclinical studies were conducted to characterize the pharmacokinetics and metabolism of H3B-6545 in rat and monkeys. Methods: The clearance and metabolic profiles of H3B-6545 were studied using rat, monkey and human hepatocytes, and reaction phenotyping was done using recombinant human cytochrome P450 enzymes. Blood stability, protein binding, and permeability were also determined in vitro. Pharmacokinetics of H3B-6545 was assessed after both intravenous and oral dosing. A nonclinical PBPK model was developed to assess in vitro-in vivo correlation of clearance. Results: H3B-6545 had a terminal elimination half-life of 2.4 h in rats and 4.0 h in monkeys and showed low to moderate bioavailability, in line with the in vitro permeability assessment. Plasma protein binding was similar across species, at 99.5-99.8%. Nine metabolites of H3B-6545 were identified in hepatocyte incubations, none of which were unique to humans. Formation of glutathione-related conjugate of H3B-6545 was minimal in vitro. H3B-6545, a CYP3A substrate, is expected to be mostly cleared via hepatic phase 1 metabolism. Hepatocyte clearance values were used to adequately model the time-concentration profiles in rat and monkey. Conclusions: We report on the absorption and metabolic fate and disposition of H3B-6545 in rats and dogs and illustrate that in vitro-in vivo correlation of clearance is possible for targeted covalent inhibitors, provided reactivity is not a predominant mechanism of clearance.
Pharmacokinetics and metabolism of H3B-6545, a selective estrogen receptor covalent antagonist, in dog plasma by liquid chromatography combined with electrospray ionization tandem mass spectrometry
J Pharm Biomed Anal 2019 Aug 5;172:189-199.PMID:31055184DOI:10.1016/j.jpba.2019.04.045.
The present study aimed at developing a simple and sensitive LC-MS/MS assay for the determination of H3B-6545 in dog plasma. The plasma samples were processed with acetonitrile and subsequently separated on a ZORBAX SB-C18 column (50 mm × 4.6 mm, 5 μm), using 0.1% formic acid in water and acetonitrile as mobile phase, at a flow rate of 0.4 mL/min. Mass detection was obtained using selected reaction monitoring mode with precursor-to-product ion transitions at m/z 568.2→155.2 for H3B-6545 and m/z 304.1→161.1 for IS. The assay showed excellent linearity over the concentration range of 0.1-1000 ng/mL, with correlation coefficient >0.9987. The assay was demonstrated to be precise, accurate, and free of matrix effect. The sample preparation procedure offered a high extraction recovery (> 88.67%). H3B-6545 was stable in dog plasma after storage at different conditions. The newly established assay was further applied to the pharmacokinetic study of H3B-6545 in dog plasma after intravenous and oral administration, and the results revealed that H3B-6545 showed dose-independent pharmacokinetic characteristics over the dose range of 1-10 mg/kg with oral bioavailability being ˜50%. Additionally, the metabolites present in dog plasma were identified by LC-ESI-Q-Exactive-Orbitrap-MS and their identities were characterized by retention times, accurate masses and fragment ions. The metabolic pathways referred to N-demethylation, N-dealkylation, deamination, aldehyde oxidation, aldehyde reduction and formation of amide.
Characterization of the metabolites of H3B-6545 in vitro and in vivo by using ultra-high performance liquid chromatography combined with electrospray ionization linear ion trap-orbitrap tandem mass spectrometry
Biomed Chromatogr 2020 Feb;34(2):e4746.PMID:31725913DOI:10.1002/bmc.4746.
H3B-6545 is a selective ERα covalent antagonist, which has been demonstrated to be effective in anti-tumor. To fully understand its mechanism of action, it is necessary to investigate the in vitro and in vivo metabolic profiles. For in vitro metabolism, H3B-6545 (50 μM) was incubated with the hepatocytes of rat and human for 2 h. For in vivo metabolism H3B-6545 was orally administered to rats at a single dose of 10 mg/kg, and plasma, urine and fecal samples were then collected. All samples were analyzed by using ultra-high performance liquid chromatography combined with linear ion trap-orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) operated in positive ion mode. The structures of the metabolites were elucidated by comparing their MS and MS2 spectra with those of parent drug. A total of 11 metabolites, including a GSH adduct, were detected and structurally identified. M2, M7 and M8 were further unambiguously identified by using reference standards. Among these metabolites, M1, M5, M7 and M10 were newly found and reported for the first time. The metabolic pathways of H3B-6545 included deamination (M8 and M9), dealkylation (M2, M3 and M10), N-hydroxylation (M6), hydroxylation (M1 and M4), formation of amide derivatives (M5 and M7) and GSH conjugation (G1).