Zapnometinib
(Synonyms: PD0184264; ATR-002) 目录号 : GC63264
Zapnometinib (PD0184264, ATR-002), an major active metabolite of CI-1040, is a novel MEK inhibitor with an IC50 of 5.7 nM.
Cas No.:303175-44-2
Sample solution is provided at 25 µL, 10mM.
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Zapnometinib (PD0184264, ATR-002), an major active metabolite of CI-1040, is a novel MEK inhibitor with an IC50 of 5.7 nM.
[1] Martin Laure, et al. Antiviral Res . 2020 Jun;178:104806.
Cas No. | 303175-44-2 | SDF | |
别名 | PD0184264; ATR-002 | ||
分子式 | C13H7ClF2INO2 | 分子量 | 409.55 |
溶解度 | DMSO : 62.5 mg/mL (152.61 mM; Need ultrasonic) | 储存条件 | 4°C, protect from light |
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1 mg | 5 mg | 10 mg |
1 mM | 2.4417 mL | 12.2085 mL | 24.417 mL |
5 mM | 0.4883 mL | 2.4417 mL | 4.8834 mL |
10 mM | 0.2442 mL | 1.2209 mL | 2.4417 mL |
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Pharmacokinetics, absorption, distribution, metabolism and excretion of the MEK inhibitor Zapnometinib in rats
Front Pharmacol 2022 Dec 5;13:1050193.PMID:36545320DOI:10.3389/fphar.2022.1050193.
Zapnometinib is a MEK inhibitor currently under clinical development for the treatment of COVID-19 and influenza. Zapnometinib has both antiviral and immunomodulatory effects. Information concerning the absorption, distribution, metabolism, and excretion of the compound following single oral doses of 30 mg/kg [14C]-zapnometinib to rats was required to support pharmacology and toxicology studies in animals and clinical studies in man. As part of the development and safety assessment of this substance, Zapnometinib was radioactively labeled and used for the investigation of time-dependent plasma concentrations, the rates and routes of excretion, the extent and time-course of compound distribution in body tissues, the metabolite profiles in plasma, urine and feces and the chemical nature of its metabolites. The present study reveals a rapid but low absorption of Zapnometinib from the gastrointestinal tract, with more than 90% of the compound being excreted within 48 h, mainly via feces. Whole body autoradiography confirms that Zapnometinib was rapidly and widely distributed, with greatest concentrations in the circulatory and visceral tissues. Maximum plasma and tissue concentrations occurred between two and 8 h post dose. Penetration into the brain was low, and elimination from most tissues almost complete after 168 h. Metabolic profiles showed that the main clearance routes were metabolism via oxidative reactions and glucuronidation. These results further strengthen the knowledge of Zapnometinib with respect to the clinical development of the drug.
Pharmacokinetics, Pharmacodynamics and Antiviral Efficacy of the MEK Inhibitor Zapnometinib in Animal Models and in Humans
Front Pharmacol 2022 Jun 15;13:893635.PMID:35784712DOI:10.3389/fphar.2022.893635.
The mitogen-activated protein kinase (MEK) inhibitor Zapnometinib is in development to treat acute viral infections like COVID-19 and influenza. While the antiviral efficacy of Zapnometinib is well documented, further data on target engagement/pharmacodynamics (PD) and pharmacokinetics (PK) are needed. Here, we report Zapnometinib PK and PD parameters in mice, hamsters, dogs, and healthy human volunteers. Mice received 25 mg/kg/day Zapnometinib (12.5 mg/kg p. o. twice daily, 8 h interval). Syrian hamsters received 30 mg/kg (15 mg/kg twice daily) or 60 mg/kg/day once daily. Beagle dogs were administered 300 mg/kg/day, and healthy human volunteers were administered 100, 300, 600 and 900 mg Zapnometinib (once daily p. o.). Regardless of species or formulation, Zapnometinib maximum plasma concentration (Cmax) was reached between 2-4 h after administration with an elimination half-life of 4-5 h in dogs, 8 h in mice or hamsters and 19 h in human subjects. Doses were sufficient to cause up to 80% MEK inhibition. Across all species approximately 10 μg/ml Zapnometinib was appropriate to inhibit 50% of peripheral blood mononuclear cells (PBMC) MEK activity. In mice, a 50%-80% reduction of MEK activity was sufficient to reduce influenza virus titer in the lungs by more than 90%. In general, while >50% MEK inhibition was reached in vivo at most doses, 80% inhibition in PBMCs required significantly higher doses and appeared to be the practical maximal level obtained in vivo. However, the period of reduced phosphorylated extracellular-signal regulated kinase (pERK), a measure of MEK inhibition, was maintained even after elimination of Zapnometinib from plasma, suggesting a sustained effect on MEK consistent with regulatory effects or a slow off-rate. These data suggest a target plasma Cmax of at least 10 μg/ml Zapnometinib in further clinical studies.
The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs
Pharmaceutics 2022 Aug 25;14(9):1776.PMID:36145524DOI:10.3390/pharmaceutics14091776.
The coronavirus disease 2019 (COVID-19) represents a global public health burden. In addition to vaccination, safe and efficient antiviral treatment strategies to restrict the viral spread within the patient are urgently needed. An alternative approach to a single-drug therapy is the combinatory use of virus- and host-targeted antivirals, leading to a synergistic boost of the drugs' impact. In this study, we investigated the property of the MEK1/2 inhibitor ATR-002's (Zapnometinib) ability to potentiate the effect of direct-acting antivirals (DAA) against SARS-CoV-2 on viral replication. Treatment combinations of ATR-002 with nucleoside inhibitors Molnupiravir and Remdesivir or 3C-like protease inhibitors Nirmatrelvir and Ritonavir, the ingredients of the drug Paxlovid, were examined in Calu-3 cells to evaluate the advantage of their combinatory use against a SARS-CoV-2 infection. Synergistic effects could be observed for all tested combinations of ATR-002 with DAAs, as calculated by four different reference models in a concentration range that was very well-tolerated by the cells. Our results show that ATR-002 has the potential to act synergistically in combination with direct-acting antivirals, allowing for a reduction in the effective concentrations of the individual drugs and reducing side effects.
Establishment of a novel method to assess MEK1/2 inhibition in PBMCs for clinical drug development
Front Cell Dev Biol 2022 Dec 12;10:1063692.PMID:36578787DOI:10.3389/fcell.2022.1063692.
The Raf/MEK/ERK signaling pathway plays a key role in regulating cellular proliferation, differentiation, apoptosis, cytokine production, and immune responses. However, it is also involved in diseases such as cancer, and numerous viruses rely on an active Raf/MEK/ERK pathway for propagation. This pathway, and particularly MEK1/2, are therefore promising therapeutic targets. Assessment of target engagement is crucial to determine pharmacodynamics or the efficacy of a MEK1/2 inhibitor. In the field of infectious diseases, this is usually first determined in clinical trials with healthy volunteers. One method to detect MEK1/2 inhibitor target engagement is to assess the degree of ERK1/2 phosphorylation, as ERK1/2 is the only known substrate of MEK1/2. As healthy subjects, however, only feature a low baseline MEK1/2 activation and therefore low ERK1/2 phosphorylation in most tissues, assessing target engagement is challenging, and robust methods are urgently needed. We hence developed a method using PBMCs isolated from whole blood of healthy blood donors, followed by ex vivo treatment with the MEK1/2 inhibitor Zapnometinib and stimulation with PMA to first inhibit and then induce MEK1/2 activation. As PMA cannot activate MEK1/2 upon MEK1/2 inhibition, MEK1/2 inhibition results in impaired MEK1/2 activation. In contrast, PMA stimulation without MEK1/2 inhibition results in high MEK1/2 activation. We demonstrated that, without MEK1/2 inhibitor treatment, MEK1/2 stimulation with PMA induces high MEK1/2 activation, which is clearly distinguishable from baseline MEK1/2 activation in human PBMCs. Furthermore, we showed that treatment with the MEK1/2 inhibitor Zapnometinib maintains the MEK1/2 activation at approximately baseline level despite subsequent stimulation with PMA. As our protocol is easy to follow and preserves the cells in an in vivo-like condition throughout the whole handling process, this approach can be a major advance for the easy assessment of MEK1/2 inhibitor target engagement in healthy probands for clinical drug development.
MEK inhibitors as novel host-targeted antivirals with a dual-benefit mode of action against hyperinflammatory respiratory viral diseases
Curr Opin Virol 2023 Apr;59:101304.PMID:36841033DOI:10.1016/j.coviro.2023.101304.
Acute hyperinflammatory virus infections, such as influenza or coronavirus disease-19, are still a major health burden worldwide. In these diseases, a massive overproduction of pro-inflammatory cytokines and chemokines (cytokine storm syndrome) determine the severity of the disease, especially in late stages. Direct-acting antivirals against these pathogens have to be administered very early after infection to be effective and may induce viral resistance. Here, we summarize data on a host-targeted strategy using inhibitors of the cellular Raf/MEK/ERK kinase cascade that not only block replication of different RNA viruses but also suppress the hyperinflammatory cytokine response upon infection. In the first phase-II clinical trial of that approach, the MEK inhibitor Zapnometinib shows evidence of clinical benefit.