Seclidemstat (SP-2577)
(Synonyms: SP-2577) 目录号 : GC32820
Seclidemstat (SP-2577) is a potent and orally bioavailable inhibitor of lysine-specific demethylase 1 (LSD1/KDM1A) with IC50 of 13 nM. Seclidemstat (SP-2577) has potential antineoplastic activity.
Cas No.:1423715-37-0
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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- SDS (Safety Data Sheet)
- Datasheet
Seclidemstat (SP-2577) is a potent and orally bioavailable inhibitor of lysine-specific demethylase 1 (LSD1/KDM1A) with IC50 of 13 nM. Seclidemstat (SP-2577) has potential antineoplastic activity.
The combination therapy of Seclidemstat (SP-2577) with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers. Seclidemstat promotes endogenous retroviruses (ERVs) expression and activation of IFNβ pathway in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) cell lines. Seclidemstat (3 μM) promotes PD-L1 expression in SCCOHT COV 434 pIND 20 BRG1-2.7 cell line.[1]
[1] Soldi R, et al. PLoS One. 2020 Jul 10;15(7):e0235705. [2] Hariprasad V, et al. WO 2017004519 A1.
| Cas No. | 1423715-37-0 | SDF | |
| 别名 | SP-2577 | ||
| Canonical SMILES | O=C(N/N=C(C1=CC(Cl)=CC=C1O)\C)C2=CC=CC(S(=O)(N3CCN(C)CC3)=O)=C2 | ||
| 分子式 | C20H23ClN4O4S | 分子量 | 450.94 |
| 溶解度 | DMSO : 100 mg/mL (221.76 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 2.2176 mL | 11.0879 mL | 22.1759 mL |
| 5 mM | 0.4435 mL | 2.2176 mL | 4.4352 mL |
| 10 mM | 0.2218 mL | 1.1088 mL | 2.2176 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。
In vivo evaluation of the lysine-specific demethylase (KDM1A/LSD1) inhibitor SP-2577 (Seclidemstat) against pediatric sarcoma preclinical models: A report from the Pediatric Preclinical Testing Consortium (PPTC)
Pediatr Blood Cancer 2021 Nov;68(11):e29304.PMID:34453478DOI:10.1002/pbc.29304.
SP-2577(Seclidemstat), an inhibitor of lysine-specific demthylase KDM1A (LSD1) that is overexpressed in pediatric sarcomas, was evaluated against pediatric sarcoma xenografts. SP-2577 (100 mg/kg/day × 28 days) statistically significantly (p < .05) inhibited growth of three of eight Ewing sarcoma (EwS), four of five rhabdomyosarcoma (RMS), and four of six osteosarcoma (OS) xenografts. The increase in EFS T/C was modest (<1.5) for all models except RMS Rh10 (EFS T/C = 2.8). There were no tumor regressions or consistent changes in dimethyl histone H3(K4), HOXM1, DAX1, c-MYC and N-MYC, or tumor histology/differentiation. SP-2577 has limited activity against these pediatric sarcoma models at the dose and schedule evaluated.
The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer
PLoS One 2020 Jul 10;15(7):e0235705.PMID:32649682DOI:10.1371/journal.pone.0235705.
Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates the chromatin landscape and gene expression by demethylating proteins such as histone H3. Cross-cancer analysis of the TCGA database shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. SCCOHT and OCCC cell lines have shown sensitivity to the reversible LSD1 inhibitor SP-2577 (Seclidemstat), suggesting that SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Moreover, it has been shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of endogenous retroviral elements and may thereby overcome resistance to checkpoint blockade. In this study, we investigated the ability of SP-2577 to promote anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC cell lines. We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.
Scaffolding LSD1 Inhibitors Impair NK Cell Metabolism and Cytotoxic Function Through Depletion of Glutathione
Front Immunol 2020 Sep 17;11:2196.PMID:33042135DOI:10.3389/fimmu.2020.02196.
Cell therapies such as chimeric-antigen receptor (CAR) T-cells and NK cells are cutting-edge methods for treating cancer and other diseases. There is high interest in optimizing drug treatment regimens to best work together with emerging cell therapies, such as targeting epigenetic enzymes to stimulate recognition of tumor cells by immune cells. Herein, we uncover new mechanisms of the histone demethylase LSD1, and various inhibitors targeting unique domains of LSD1, in the function of NK cells grown for cell therapy. Catalytic inhibitors (tranylcypromine and the structural derivatives GSK LSD1 and RN-1) can irreversibly block the demethylase activity of LSD1, while scaffolding inhibitors (SP-2509 and clinical successor SP-2577, also known as Seclidemstat) disrupt epigenetic complexes that include LSD1. Relevant combinations of LSD1 inhibitors with cell therapy infusions and immune checkpoint blockade have shown efficacy in pre-clinical solid tumor models, reinforcing a need to understand how these drugs would impact T- and NK cells. We find that scaffolding LSD1 inhibitors potently reduce oxidative phosphorylation and glycolysis of NK cells, and higher doses induce mitochondrial reactive oxygen species and depletion of the antioxidant glutathione. These effects are unique to scaffolding inhibitors compared to catalytic, to NK cells compared to T-cells, and importantly, can fully ablate the lytic capacity of NK cells. Supplementation with biologically achievable levels of glutathione rescues NK cell cytolytic function but not NK cell metabolism. Our results suggest glutathione supplementation may reverse NK cell activity suppression in patients treated with Seclidemstat.
LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials
Front Pharmacol 2023 Feb 2;14:1120911.PMID:36817147DOI:10.3389/fphar.2023.1120911.
Histone lysine-specific demethylase 1 (LSD1/KDM1A) was first identified in 2004 as an epigenetic enzyme able to demethylate specific lysine residues of histone H3, namely H3K4me1/2 and H3K9me1/2, using FAD as the cofactor. It is ubiquitously overexpressed in many types of cancers (breast, gastric, prostate, hepatocellular, and esophageal cancer, acute myeloid leukemia, and others) leading to block of differentiation and increase of proliferation, migration and invasiveness at cellular level. LSD1 inhibitors can be grouped in covalent and non-covalent agents. Each group includes some hybrid compounds, able to inhibit LSD1 in addition to other target(s) at the same time (dual or multitargeting compounds). To date, 9 LSD1 inhibitors have entered clinical trials, for hematological and/or solid cancers. Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and Seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents.
Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology
ACS Pharmacol Transl Sci 2021 Nov 12;4(6):1818-1834.PMID:34927013DOI:10.1021/acsptsci.1c00223.
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (Seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.