A new chemotype inhibitor for the human organic cation transporter 3 (hOCT3)

Pan, Xiaolei; Iyer, Kavita A.; Liu, Hebing; Sweet, Douglas H.; Dukat, Małgorzata

doi:10.1016/j.bmcl.2017.08.008

Cited by 6 publications

(6 citation statements)

References 29 publications

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“…To develop a new potent and selective OCT ligand, 3D homology models of the human α2adrenergic receptor (Figure1b), an unwanted target, and of human OCT2 (Figure 1c) were generated from selected templates (Figure b-d). The OCT2 model generated was coherent with previous models 25,26 , and interactions defined in functional studies 16,27,28 . By comparing positioning and interactions of D24 in both models, we modified this compound to introduce a bulky substituent hindering interaction with the α2C adrenoceptor, thereby generating the analog cyanome (Figure 1a).…”

Section: Development Of a Selective Oct Prodrugsupporting

confidence: 68%

Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

et al. 2019

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Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. In a rodent model of chronic depression induced by corticosterone exposure, daily administration of this compound, H2-cyanome, induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased VTA dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome also modulated in a similar way than fluoxetine several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of long-term antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.

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Section: Development Of a Selective Oct Prodrugsupporting

confidence: 68%

Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

et al. 2019

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“…By contrast, parameters such as lipophilicity (LogP) or TPSA are correlated with inhibition of OCT1 and OCT2, but not with blockage of OCT3 by heterocyclic aromatic amines [19] or by TKIs [14] (Table S1). This lack of contribution of lipophilicity to OCT3 inhibition however likely merits complementary investigations because it is challenged by the enhanced inhibitory potency of phenylguanidines with increased lipophilic character toward OCT3 activity [39]. Excessive lipophilicity may nevertheless make it difficult for a TKI to access the substrate‐binding region of OCT3 in contact with the aqueous phase, as already proposed for OCT1 [14].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of organic cation transporter 3 activity by tyrosine kinase inhibitors

Alim

Moreau

Bruyère

et al. 2021

Fundamemntal Clinical Pharma

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Organic cation transporter (OCT) 3 (SLC22A3) is a widely expressed drug transporter, handling notably metformin and platinum derivatives, as well as endogenous compounds like monoamine neurotransmitters. OCT3 has been shown to be inhibited by a few marketed tyrosine kinase inhibitors (TKIs). The present study was designed to determine whether additional TKIs may interact with OCT3. For this purpose, the effects of 25 TKIs toward OCT3 activity were analyzed using OCT3overexpressing HEK293 cells. 13/25 TKIs, each used at 10 µM, were found to behave as moderate or strong inhibitors of OCT3 activity, that is, they decreased OCT3-mediated uptake of the fluorescent dye 4-(4-(dimethylamino)styryl)-Nmethylpyridinium iodide by at least 50% or 80%, respectively. This OCT3 inhibition was correlated to some molecular descriptors of TKIs, such as the percentage of H atoms and that of cationic forms at pH = 7.4. It was concentration-dependent, notably for brigatinib, ceritinib, and crizotinib, which exhibited low half maximal inhibitory concentration (IC 50 ) values in the 28-106 nM range. Clinical concentrations of these three marketed TKIs, as well as those of pacritinib, were next predicted to inhibit in vivo OCT3 activity according to regulatory criteria. Cellular TKI accumulation experiments as well as trans-stimulation assays, however, demonstrated that OCT3 does not transport brigatinib, ceritinib, crizotinib, and pacritinib, thus discarding any implication of OCT3 in the pharmacokinetics of these TKIs. Taken together, these data suggest that some TKIs may act as potent inhibitors of OCT3 activity, which may have consequences in terms of drug-drug interactions and toxicity.

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“…In conclusion, OCT3 may directly inhibit the malignant biological behavior of cancer and may be considered a novel target for intervention in CRC. OCT3-specific inhibitors have recently been reported (33,34), and will be useful tools for further investigating the function of OCT3.…”

Section: Discussionmentioning

confidence: 99%

Role and mechanism of organic cation transporter 3 in oxaliplatin treatment of colon cancer in vitro and in vivo

Li²,

Tang

et al. 2019

Oncol Rep

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Oxaliplatin (OXA) is routinely used as the first-line treatment for colorectal cancer (CRC). The addition of OXA to chemotherapy has significantly improved the prognosis of patients with CRC; however, some cases are resistant to OXA. The present study explored the influence of organic cation transporter 3 (OCT3) expression on the effects of OXA on CRC cell viability, and investigated the direct effects of OCT3 on viability, invasion and migration of CRC cells using MTT assay, wound healing assay, reverse transcription-quantitative polymerase chain reaction, inductively coupled plasma mass spectrometry and lentiviral interference. The results demonstrated that OXA cellular concentration and OXA-induced cytotoxicity were significantly increased in response to high expression of OCT3, whereas OCT3 knockdown directly increased the invasion and migration of colon cancer cells. Furthermore, upregulation of OCT3 expression in colon cancer xenografts via treatment with the DNA methyltransferase inhibitor decitabine increased cellular OXA concentration and improved the curative effect of OXA. These results collectively indicated that OCT3 may enhance the effects of OXA in CRC cells and may directly inhibit their invasion and migration. Therefore, OCT3 may be a therapeutic target in patients with CRC.

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A new chemotype inhibitor for the human organic cation transporter 3 (hOCT3)

Cited by 6 publications

References 29 publications

Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

Inhibition of organic cation transporter 3 activity by tyrosine kinase inhibitors

Role and mechanism of organic cation transporter 3 in oxaliplatin treatment of colon cancer in vitro and in vivo

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