SNDX-5613
(Synonyms: SNDX-5613) 目录号 : GC39508
SNDX-5613 is a potent and selective inhibitor of menin-MLL binding with a Ki of 0.15 nM. SNDX-5613 shows anti-proliferative activity against multiple cell lines harboring MLLr translocations (MV4;11, RS4;11, MOLM-13, KOPN-8) with IC50 values ranging from 10-20 nM.
Cas No.:2169919-21-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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- Datasheet
SNDX-5613 is a potent and selective inhibitor of menin-MLL binding with a Ki of 0.15 nM. SNDX-5613 shows anti-proliferative activity against multiple cell lines harboring MLLr translocations (MV4;11, RS4;11, MOLM-13, KOPN-8) with IC50 values ranging from 10-20 nM.
SNDX-5613 has anti-proliferative activity against multiple cell lines harboring MLLr translocations (MV4;11, RS4;11, MOLM-13, KOPN-8). SNDX-5613 doesn't inhibit growth of HL-60, a promyelocytic leukemia cell line lacking an MLL rearrangement , indicating selective activity towards leukemic cells lines that harbor MLL-rearranged (MLLr) fusion proteins.[1]
SNDX-5613 treatment provides significant survival benefit and leukemic control in aggressive MOLM-13 xenografts nude rats.[1]
[1] SNDX-5613 Briefing Document for the 18 June 2020 Oncologic Drugs Advisory Committee Pediatric Subcommittee
| Cas No. | 2169919-21-3 | SDF | |
| 别名 | SNDX-5613 | ||
| Canonical SMILES | O=C(N(CC)C(C)C)C1=CC(F)=CC=C1OC2=CN=CN=C2N3CC4(CCN(C[C@H]5CC[C@H](NS(=O)(CC)=O)CC5)CC4)C3 | ||
| 分子式 | C32H47FN6O4S | 分子量 | 630.82 |
| 溶解度 | DMSO: 41.67 mg/mL (66.06 mM) | 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 | 1.5852 mL | 7.9262 mL | 15.8524 mL |
| 5 mM | 0.317 mL | 1.5852 mL | 3.1705 mL |
| 10 mM | 0.1585 mL | 0.7926 mL | 1.5852 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。
Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)
Blood Cancer J 2022 Jan 11;12(1):5.PMID:35017466DOI:10.1038/s41408-021-00603-3.
Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.
Menin-MLL protein-protein interaction inhibitors: a patent review (2014-2021)
Expert Opin Ther Pat 2022 May;32(5):507-522.PMID:35202550DOI:10.1080/13543776.2022.2045947.
Introduction: Chromosomal translocations involving the mixed-lineage leukemia (MLL, KMT2A, MLL1) genes result in the production of MLL fusion proteins, which cause abnormal transcriptional regulation leading to acute leukemia (AL). Menin (MEN1) protein is essential for MLL to regulate the expression of related target genes. High-affinity interactions between the amino terminus of MLL proteins and Menin proteins are required to mediate the oncogenic transformation of MLL fusion proteins. Therefore, inhibition of Menin and MLL interaction is a potential therapeutic strategy for MLL rearrangement (MLL-r) leukemia and can provide a new choice for treatment of other diseases. Therefore, researchers have made great efforts to explore small-molecule Menin-MLL interaction inhibitors. Areas covered: This review is to provide an overview of the patented Menin-MLL protein-protein interaction inhibitors from 2014 to 2021. Expert opinion: Menin-MLL interaction inhibitors have therapeutic potential in the treatment of acute leukemia, such as AML and ALL. SNDX-5613 and KO-539 have been granted orphan drug designation by the FDA for treatment of refractory/relapsed leukemia and AML, respectively. In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
Nature 2023 Mar;615(7954):920-924.PMID:36922593DOI:10.1038/s41586-023-05812-3.
Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting
J Hematol Oncol 2023 Mar 3;16(1):17.PMID:36869366DOI:10.1186/s13045-023-01411-x.
Developments in investigational agents and novel regimens in acute myeloid leukemia (AML) were reported in the 2022 American Society of Hematology (ASH) annual meeting. Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody-drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.