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Nature
610.7931 (2022): 366-372

Nature
618, 1017–1023 (2023)

Cell
183.7 (2020): 1867-1883

Cell Research
31, 1291–1307 (2021)

Cell Research
33, 273–287 (2023)

Cell Research
33, 546–561 (2023)

Molecular Cancer
21.1 (2022): 1-17

Molecular Cancer
21.1 (2022): 1-18

Cancer Cell
39 (2021): 1-16

Cell Host Microbe
30.8 (2022): 1124-1138

Cell Host Microbe
31.5 (2023): 766-780

Cell Host Microbe
31.3 (2023): 418-43

Cell Metabolism
34.2 (2022): 240-255

Ann Rheum Dis
82(4): 533-545 (2023)

Cell Mol Immunol
20, 264–276 (2023)

Adv Funct Mater
33.35 (2023): 2214998

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Purity: >98.00%

实验参考方法

Cell experiment [1]:
Cell lines	DLD-1, HT29, SW620 and HCT116 CRC cell lines and the non-tumourigenic CCD-841 cell line
Preparation Method	6000 cells/well were seeded into 96- well flat-bottom plates and incubated for 24 h under standard conditions. MN58b or RSM-932A (TCD-717) were added at different concentrations from stocks solutions.
Reaction Conditions	2, 3, 4 µM, 24h
Applications	RSM-932A (TCD-717; 2-4 µM; for 24 hours) promotes cell death of colon cancer cells. ChoKα specific inhibitor RSM-932A (TCD-717), has demonstrated a potent antitumoral activity both in vitro and in vivo against several tumor-derived cell line xenografts including CRC-derived cell lines.
Animal experiment [2]:
Animal models	Six-week-old nude mice
Preparation Method	Mice were s.c. inoculated at lowers flanks with 1 × 106 of HT-29 cells suspended in 100μL of serum-free DMEM media mixed (1:1) with Matrigel. Measurable subcutaneous tumors (~0.15-0.2 cm3) were randomized to the treatment and control group. Tumor growth was monitored three times per week.
Dosage form	Effective dose of RSM-932A is 7.5 mg/kg, RSM-932A was dissolved at 50 mM 100% DMSO and administrated by i.v.. The successive dilutions were done fresh every day of treatment in sterile 5% dextrose water.
Applications	This could be used to perform growth inhibition studies at the specified effective dose. No significant organ damage was observed apart from hepatotoxicity that was found in all treatments except for the less aggressive treatment with RSM-932A that showed no liver toxicity while retaining a potent antitumoral activity.
References: [1]. de la Cueva A, et al. Combined 5-FU and ChoKα inhibitors as a new alternative therapy of colorectal cancer: evidence in human tumor-derived cell lines and mouse xenografts. PLoS One. 2013 Jun 10;8(6):e64961. [2]. Lacal JC, et al. Preclinical characterization of RSM-932A, a novel anticancer drug targeting the human choline kinase alpha, an enzyme involved in increased lipid metabolism of cancer cells. Mol Cancer Ther. 2015 Jan;14(1):31-9.

产品描述

RSM-932A is a ChoKα inhibitor with potent in vitro antiproliferative activity against a large variety of tumor-derived cell lines and in vivo antitumoral activity against human xenographs in mice. RSM-932A also shows high efficacy with low toxicity at the effective doses.^[1]

In vitro experiments indicated that RSM-932A has a potent antiproliferative activity against most tumor-derived cell lines tested, including those derived from breast, lung, colon, bladder, liver, ovary, bone, cervix, kidney, pancreas, melanoma and brain tumors, with IC50 (1.15 ± 0.14 μM) in the low, single-digit micromolar range, consistent with a cytotoxic effect.

		RSM-932A (72 h)
Type of tumor	Cell line	IC₅₀	±SD	GI₅₀	±SD	TGI	±SD	LC₅₀	±SD
Breast?	MDA-MB-231?	1.3?	0.5?	1.2?	0.2?	2.0?	0.1?	2.7?	1.2?
	T47D?	2,2?	0,9?	1,3?	0,8?	NA?	NA?	>6?	NA?
	MDA.MB.468?	2.4?	1.0?	1.6?	0.4?	3.1?	1.6?	>6?	0.5?
	SkBr-3?	3.1?	0.6?	1.0?	0.6?	1.6?	0.5?	13.2?	6.7?
Lung?	H510?	1.4?	0.3?	1.0?	NA?	1.1?	0.5?	3.9?	1.8?
	H1299?	1.9?	0.1?	1.0?	0.0?	1.9?	0.7?	7.4?	3.0?
	H460?	1.9?	0.5?	1.0?	0.0?	1.7?	0.6?	5.2?	1.3?
Colon?	HT-29?	1.7?	0.4?	1.3?	0.2?	5.6?	6.6?	11.0?	5.4?
	HCT-116?	1.8?	0.3?	1.0?	0.3?	1.7?	1.0?	>6?	NA?
	DLD-1?	2.1?	0.7?	1.6?	0.5?	3.3?	0.9?	6.3?	2.8?
	SW620?	2.1?	0.7?	1.6?	0.5?	3.3?	0.9?	6.3?	2.8?
Bladder?	HT-1376?	1.5?	0.3?	1.0?	0.0?	5.7?	1.2?	>6.5?	NA?
	TccSup?	1.6?	0.2?	1.1?	0.5?	1.5?	0.0?	>6.5?	NA?
	SW780?	1.6?	0.4?	1.4?	0.3?	2.3?	0.5?	8.2?	3.1?
	J82?	2.3?	1.3?	1.6?	1.2?	NA?	NA?	5.0?	2.1?
Epithelial carcinoma?	A431?	2.2?	0.1?	1.5?	0.5?	NA?	NA?	3.5?	0.7?
Liver?	Hep3B2?	2.4?	0.5?	1.2?	0.1?	2.7?	1.4?	3.2?	0.8?
	HepG2?	6.4?	2.2?	1.3?	0.3?	8.4?	1.3?	>12?	NA?
Ovary?	OV-Car-3?	3.4?	0.3?	1.7?	0.2?	2.9?	0.4?	5.5?	0.5?
	SK-OV-3?	6.4?	2.2?	1.3?	0.3?	8.4?	1.3?	>12?	NA?
Bone?	SAOS-2?	1.3?	0.1?	<1.6?	NA?	2.2?	0.7?	5.1?	1.5?
Cervix?	HeLa?	1.7?	0.7?	1.0?	NA?	1.5?	0.0?	5.7?	1.2?
Kidney?	769-P?	1.4?	0.2?	1.0?	0.4?	2.4?	1.2?	>3.5?	0.7?
Melanoma?	SKMel-28?	1.3?	0.3?	0.5?	0.0?	0.4?	0.1?	1.5?	0.4?
	A-375?	6.2?	1.9?	2.6?	1.4?	5.6?	1.1?	7.7?	1.4?
Pancreas?	Mia.PaCa.2?	2.3?	0.2?	1.7?	0.3?	3.5?	0.4?	5.5?	1.4?
Astrocytoma, gliocystoma?	U-87?	1.9?	0.5?	1.4?	0.2?	5.0?	1.2?	8.9?	4.3?
Control?	MCF10-A?	7.1?	0.5?	3.4?	0.8?	7.2?	1.3?	14.7?	1.3?

Table 1.Panel of human cancer cell lines tested with RSM-932A for 72 hours and determination of IC₅₀, GI₅₀, TGI, and LC₅₀ parameters

In vivo experiments demonstrated that RSM-932A shows no detectable toxicity in mice at highly effective doses with 77% tumor growth inhibition.^[1]

References:
[1]. Lacal JC, et al. Preclinical characterization of RSM-932A, a novel anticancer drug targeting the human choline kinase alpha, an enzyme involved in increased lipid metabolism of cancer cells. Mol Cancer Ther. 2015 Jan;14(1):31-9.

RSM-932A 是一种 ChoKα 抑制剂，对多种肿瘤来源的细胞系具有有效的体外抗增殖活性，对小鼠的人异种移植物具有体内抗肿瘤活性。 RSM-932A 在有效剂量下也表现出高效低毒。^[1]

体外实验表明，RSM-932A 对测试的大多数肿瘤衍生细胞系具有有效的抗增殖活性，包括来自乳腺、肺、结肠、膀胱、肝脏、卵巢、骨骼、子宫颈、肾脏、胰腺、黑色素瘤的细胞系和脑肿瘤，IC50 (1.15 ± 0.14 μM) 在低个位数微摩尔范围内，与细胞毒性作用一致。

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Chemical Properties

Cas No.	850807-63-5	SDF
别名	TCD-717
化学名	1,1'-[[[1,1'-biphenyl]-4,4'-diyl]bis(methylene)]bis[4-[(4-chlorophenyl)methylamino]-quinolinium, dibromide
Canonical SMILES	ClC1=CC=C(N(C2=CC=[N+](CC3=CC=C(C4=CC=C(C[N+]5=C(C=CC=C6)C6=C(N(C7=CC=C(Cl)C=C7)C)C=C5)C=C4)C=C3)C8=C2C=CC=C8)C)C=C1.[Br-].[Br-]
分子式	C₄₆H₃₈Cl₂N₄.2Br	分子量	877.5
溶解度	3mg/mL 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。
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。

溶解性数据

制备储备液
		1 mg	5 mg	10 mg
	1 mM	1.1396 mL	5.698 mL	11.396 mL
	5 mM	0.2279 mL	1.1396 mL	2.2792 mL
	10 mM	0.114 mL	0.5698 mL	1.1396 mL

摩尔浓度计算器
稀释计算器
分子量计算器

计算

动物体内配方计算器 (澄清溶液)

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，注：如该浓度超过该批次药物DMSO溶解度，请先联系GLPBIO）；

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。

注意：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。

Research Update

Identification and validation of novel and more effective choline kinase inhibitors against Streptococcus pneumoniae

Sci Rep2020 Sep 22;10(1):15418.PMID: 32963303DOI: 10.1038/s41598-020-72165-6

Streptococcus pneumoniae choline kinase (sChoK) has previously been proposed as a drug target, yet the effectiveness of the first and only known inhibitor of sChoK, HC-3, is in the millimolar range. The aim of this study was thus to further validate sChoK as a potential therapeutic target by discovering more powerful sChoK inhibitors. LDH/PK and colorimetric enzymatic assays revealed two promising sChoK inhibitor leads RSM-932A and MN58b that were discovered with IC50 of 0.5 and 150 μM, respectively, and were shown to be 2-4 magnitudes more potent than the previously discovered inhibitor HC-3. Culture assays showed that the minimum inhibitory concentration (MIC) of RSM-932A and MN58b for S. pneumoniae was 0.4 μM and 10 μM, respectively, and the minimum lethal concentration (MLC) was 1.6 μM and 20 μM, respectively. Western blot monitoring of teichoic acid production revealed differential patterns in response to each inhibitor. In addition, both inhibitors possessed a bacteriostatic mechanism of action, and neither interfered with the autolytic effects of vancomycin. Cells treated with MN58b but not RSM-932A were more sensitive to a phosphate induced autolysis with respect to the untreated cells. SEM studies revealed that MN58b distorted the cell wall, a result consistent with the apparent teichoic acid changes. Two novel and more highly potent putative inhibitors of sChoK, MN58b and RSM-932A, were characterized in this study. However, the effects of sChoK inhibitors can vary at the cellular level. sChoK inhibition is a promising avenue to follow in the development of therapeutics for treatment of S. pneumoniae.

Antiplasmodial activity and mechanism of action of RSM-932A, a promising synergistic inhibitor of Plasmodium falciparum choline kinase

Antimicrob Agents Chemother2013 Dec;57(12):5878-88.PMID: 24041883DOI: 10.1128/AAC.00920-13

We have investigated the mechanism of action of inhibition of the choline kinase of P. falciparum (p.f.-ChoK) by two inhibitors of the human ChoKα, MN58b and RSM-932A, which have previously been shown to be potent antitumoral agents. The efficacy of these inhibitors against p.f.-ChoK is investigated using enzymatic and in vitro assays. While MN58b may enter the choline/phosphocholine binding site, RSM-932A appears to have an altogether novel mechanism of inhibition and is synergistic with respect to both choline and ATP. A model of inhibition for RSM-932A in which this inhibitor traps p.f.-ChoK in a phosphorylated intermediate state blocking phosphate transfer to choline is presented. Importantly, MN58b and RSM-932A have in vitro inhibitory activity in the low nanomolar range and are equally effective against chloroquine-sensitive and chloroquine-resistant strains. RSM-932A and MN58b significantly reduced parasitemia and induced the accumulation of trophozoites and schizonts, blocking intraerythrocytic development and interfering with parasite egress or invasion, suggesting a delay of the parasite maturation stage. The present data provide two new potent structures for the development of antimalarial compounds and validate p.f.-ChoK as an accessible drug target against the parasite.

Preclinical characterization of RSM-932A, a novel anticancer drug targeting the human choline kinase alpha, an enzyme involved in increased lipid metabolism of cancer cells

Mol Cancer Ther2015 Jan;14(1):31-9.PMID: 25487918DOI: 10.1158/1535-7163.MCT-14-0531

Choline kinase α (CHKA; here designated as ChoKα) is the first enzyme in the CDP-choline pathway, implicated in phospholipids metabolism. It is overexpressed in several human tumors such as breast, lung, bladder, colorectal, prostate, ovary, and liver. The overexpression of ChoKα has oncogenic potential and synergizes with other known oncogenes. It has been proposed as a novel cancer drug target with a distinct mechanism of action. We have generated a set of ChoKα inhibitors with potent in vitro antiproliferative and in vivo antitumoral activity against human xenografts in mice, showing high efficacy with low toxicity profiles. Among these inhibitors, RSM-932A has been chosen for further clinical development due to its potent antiproliferative activity in vitro against a large variety of tumor-derived cell lines, a potent in vivo anticancer activity, and lack of toxicity at the effective doses. Here, we provide the preclinical evidence to support the use of RSM-932A as a good candidate to be tested in clinical trials as the "first in humans" drug targeting ChoKα.

RSM-932A

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