KDU691
目录号 : GC32118
An antimalarial compound
Cas No.:1513879-19-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | For in vivo PK studies, female CD-1 mice (25 to 30g) are used and randomly assigned to cages. Mice are allowed to acclimate before initiation of the experiments. Feed and water are given ad libitum. KDU691 is formulated at concentrations of 2.5 mg/mL and 0.25 mg/mL for a dose of 25 mg/kg and 2.5 mg/kg, respectively. The suspension formulation for p.o. dosing contains 0.5% Methyl cellulose and 0.5% Tween 80 in water. After oral dosing, blood and liver samples from mice are collected at 0.08 to 24 h post dosing. Groups of three mice are used for each time point. Blood is centrifuged at 13,000 rpm for 7 min at 4°C, plasma harvested and stored at -20°C until analysis. Liver tissue samples are excised, dipped in PBS, gently blotted with absorbent paper, dried, weighed and stored at -20°C until further analysis[1]. |
References: [1]. Zeeman AM, et al. PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2858-63. | |
KDU691 is an antimalarial compound.1 It inhibits recombinant P. vivax phosphatidylinositol 4-kinase (PI4K) with an IC50 value of 1.5 nM. KDU691 is selective for P. vivax PI4K over recombinant human PI4KβIII and PI3Kα, -β, -?, and -δ (IC50s = 7.9, 8.8, 2.4, 8, and 3.4 ?M, respectively), as well as VPS34 (IC50 = >9.7 ?M) and 36 additional kinases in a panel of lipid and protein kinases (IC50s = >10 ?M). It is active against P. falciparum and P. yoelii schizonts (IC50s = 0.06 and 0.04 ?M, respectively), as well as P. cynomolgi schizonts and hypnozoites (IC50s = 0.11 and 0.2 ?M, respectively).2 KDU691 completely prevents, but does not eradicate established, P. cynomolgi infection in rhesus monkeys when administered at a dose of 20 mg/kg.3
1.McNamara, C.W., Lee, M.C., Lim, C.S., et al.Targeting Plasmodium phosphatidylinositol 4-kinase to eliminate malariaNature504(7479)248-253(2013) 2.Zou, B., Nagle, A., Chatterjee, A.K., et al.Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stagesACS Med. Chem. Lett.5(8)947-950(2014) 3.Zeeman, A.M., Lakshminarayana, S.B., van der Werff, N., et al.PI4 kinase is a prophylactic but not radical curative target in Plasmodium vivax-type malaria parasitesAntimicrob. Agents Chemother.60(5)2858-2863(2016)
| Cas No. | 1513879-19-0 | SDF | |
| Canonical SMILES | ClC1=CC=C(N(C(C2=CN3C(C=N2)=NC=C3C4=CC=C(C(NC)=O)C=C4)=O)C)C=C1 | ||
| 分子式 | C22H18ClN5O2 | 分子量 | 419.86 |
| 溶解度 | DMSO : 150 mg/mL (357.26 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.3817 mL | 11.9087 mL | 23.8175 mL |
| 5 mM | 0.4763 mL | 2.3817 mL | 4.7635 mL |
| 10 mM | 0.2382 mL | 1.1909 mL | 2.3817 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。
The Plasmodium PI(4)K inhibitor KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites
Sci Rep2017 May 24;7(1):2325.PMID:28539634DOI:10.1038/s41598-017-02440-6.
Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance. Here, we evaluate the in vitro drug sensitivity profile of normally-developing P. falciparum ring stages and DHA-pretreated dormant rings (DP-rings) using a panel of antimalarial drugs, including the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. We report that while KDU691 shows no activity against rings, it is highly inhibitory against DP-rings; a drug effect opposite to that of ART. Moreover, we provide evidence that KDU691 also kills DP-rings of P. falciparum ART-resistant strains expressing mutant K13.
Plasmodium malariae and Plasmodium falciparum comparative susceptibility to antimalarial drugs in Mali
J Antimicrob Chemother2021 Jul 15;76(8):2079-2087.PMID:34021751DOI:10.1093/jac/dkab133.
Objectives: To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs. Methods: We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. Results: We report a high frequency (3%-15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum. Conclusions: Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.
PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites
Antimicrob Agents Chemother2016 Apr 22;60(5):2858-63.PMID:26926645DOI:10.1128/AAC.03080-15.
Two Plasmodium PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic and radical-cure agents for Plasmodium cynomolgi sporozoite-infected rhesus macaques, based on their in vitro activity against liver stages. Animals were infected with P. cynomolgi sporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on our in vitro data. These findings indicate that Plasmodium PI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer in vitro culture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure in vivo.
A Novel Ex Vivo Drug Assay for Assessing the Transmission-Blocking Activity of Compounds on Field-Isolated Plasmodium falciparum Gametocytes
Antimicrob Agents Chemother2022 Dec 20;66(12):e0100122.PMID:36321830DOI:10.1128/aac.01001-22.
The discovery and development of transmission-blocking therapies challenge malaria elimination and necessitate standard and reproducible bioassays to measure the blocking properties of antimalarial drugs and candidate compounds. Most of the current bioassays evaluating the transmission-blocking activity of compounds rely on laboratory-adapted Plasmodium strains. Transmission-blocking data from clinical gametocyte isolates could help select novel transmission-blocking candidates for further development. Using freshly collected Plasmodium falciparum gametocytes from asymptomatic individuals, we first optimized ex vivo culture conditions to improve gametocyte viability and infectiousness by testing several culture parameters. We next pre-exposed ex vivo field-isolated gametocytes to chloroquine, dihydroartemisinin, primaquine, KDU691, GNF179, and oryzalin for 48 h prior to direct membrane feeding. We measured the activity of the drug on the ability of gametocytes to resume the sexual life cycle in Anopheles after drug exposure. Using 57 blood samples collected from Malian volunteers aged 6 to 15 years, we demonstrate that the infectivity of freshly collected field gametocytes can be preserved and improved ex vivo in a culture medium supplemented with 10% horse serum at 4% hematocrit for 48 h. Moreover, our optimized drug assay displays the weak transmission-blocking activity of chloroquine and dihydroartemisinin, while primaquine and oryzalin exhibited a transmission-blocking activity of ~50% at 1 μM. KDU691 and GNF179 both interrupted Plasmodium transmission at 1 μM and 5 nM, respectively. This new approach, if implemented, has the potential to accelerate the screening of compounds with transmission-blocking activity.
Developing Plasmodium vivax Resources for Liver Stage Study in the Peruvian Amazon Region
ACS Infect Dis2018 Apr 13;4(4):531-540.PMID:29542317DOI:10.1021/acsinfecdis.7b00198.
To develop new drugs and vaccines for malaria elimination, it will be necessary to discover biological interventions, including small molecules that act against Plasmodium vivax exoerythrocytic forms. However, a robust in vitro culture system for P. vivax is still lacking. Thus, to study exoerythrocytic forms, researchers must have simultaneous access to fresh, temperature-controlled patient blood samples, as well as an anopheline mosquito colony. In addition, researchers must rely on native mosquito species to avoid introducing a potentially dangerous invasive species into a malaria-endemic region. Here, we report an in vitro culture system carried out on site in a malaria-endemic region for liver stage parasites of P. vivax sporozoites obtained from An. darlingi, the main malaria vector in the Americas. P. vivax sporozoites were obtained by dissection of salivary glands from infected An. darlingi mosquitoes and purified by Accudenz density gradient centrifugation. HC04 liver cells were exposed to P. vivax sporozoites and cultured up to 9 days. To overcome low P. vivax patient parasitemias, potentially lower mosquito vectorial capacity, and humid, nonsterile environmental conditions, a new antibiotic cocktail was included in tissue culture to prevent contamination. Culturing conditions supported exoerythrocytic (EEF) P. vivax liver stage growth up to 9 days and allowed for maturation into intrahepatocyte merosomes. Some of the identified small forms were resistant to atovaquone (1 μM) but sensitive to the phosphatidylinositol 4-kinase inhibitor, KDU691 (1 μM). This study reports a field-accessible EEF production process for drug discovery in a malaria-endemic site in which viable P. vivax sporozoites are used for drug studies using hepatocyte infection. Our data demonstrate that the development of meaningful, field-based resources for P. vivax liver stage drug screening and liver stage human malaria experimentation in the Amazon region is feasible.