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Summary Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1–3 and 8–10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose limiting toxicity (DLT) was assessed within the first treatment cycle. Tumors were evaluated, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, after two cycles. Results Twenty-three patients were treated. No drug-related serious adverse events occurred. DLTs occurred in six patients: asymptomatic, drug-related, transient Grade 2 hypocalcemia (4 patients), and unrelated Grade 3 anemia and Grade 3 atrial fibrillation, 1 patient each. Calcium and vitamin D supplementation eliminated further Grade 2 hypocalcemia. One Grade 3 treatment emergent adverse event, urticaria, was definitely related to SOR-C13. Four possibly drug-related, Grade 3 events (alanine aminotransferase and aspartate aminotransferase elevation, headache, and hypokalemia) were observed. Of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months. The best response was a 27% reduction in a pancreatic tumor with a 55% reduction in CA19–9 levels at 6.2 mg/kg. Conclusion SOR-C13 was safe and tolerated up to 6.2 mg/kg. The Maximal Tolerated Dose (MTD) was not established. Stable disease suggested antitumor activity.

Background The differential sensitivity of cough to antitussive therapies implies the existence of heterogeneity in cough hypersensitivity, but how such heterogeneity is expressed across individual patients is poorly understood. We investigated the phenotypes of cough hypersensitivity by examining transient receptor potential ankyrin 1 (TRPA1)- and transient receptor potential vanilloid 1 (TRPV1)-mediated cough sensitivity in patients with chronic refractory cough. Methods Using a selective TRPA1 agonist, allyl isothiocyanate (AITC), we established an AITC cough challenge as a measure of TRPA1-mediated cough sensitivity. The AITC cough challenge and the widely used capsaicin (a selective TRPV1 agonist) cough challenge were performed with 250 patients with chronic refractory cough and 56 healthy subjects. The concentration of AITC or capsaicin solution causing at least two (C2) and five coughs (C5) was recorded. Cough sensitivity was expressed as the mean (95% confidence interval) of log C5, and cough hypersensitivity was defined as a log C5 value lower than that of healthy subjects. Results A distinct concentration–response effect of inhaled AITC was identified both in patients with chronic refractory cough and in healthy subjects. Cough sensitivity to AITC and capsaicin was significantly higher in patients than in healthy subjects (AITC: 2.42 [2.37–2.48] vs 2.72 [2.66–2.78] mM, p  = 0.001; capsaicin: 1.87 [1.75–1.98] vs 2.53 [2.36–2.70] μM, p  = 0.001) and was higher in females than in males for both healthy subjects and patients (all p  < 0.05). Among the 234 patients who completed both challenges, 25 (10.7%) exhibited hypersensitivity to both AITC and capsaicin, 44 (18.8%) showed hypersensitivity to AITC only, 28 (11.9%) showed hypersensitivity to capsaicin only, and 137 (58.6%) exhibited hypersensitivity to neither. Those with TRPA1- and/or TRPV1-mediated hypersensitivity were predominantly female, while those without TRPA1- and TRPV1-mediated hypersensitivity were mainly male. Conclusions Four phenotypes of cough hypersensitivity were identified by the activation of TRPV1 and TRPA1 channels, which supports the existence of heterogeneity in cough pathways and provides a new direction for personalized management of chronic refractory cough. Trial registration ClinicalTrials.gov NCT02591550 .

Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms. The current work reports the structure of the human organic cation transporter 3 (OCT3 / SLC22A3) and provides the structural basis of its inhibition by two specific inhibitors, decynium-22 and corticosterone.

Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1. OCT1 plays an important role in the uptake of drugs and metabolites in the liver. Here, authors present the structure of OCT1 to understand how it recognizes and transports a wide range of drugs and substrates.

Thermosensitive transient receptor potential (TRP) ion channels detect changes in ambient temperature to regulate body temperature and temperature-dependent cellular activity. Rodent orthologs of TRP vanilloid 2 (TRPV2) are activated by nonphysiological heat exceeding 50 °C, and human TRPV2 is heat-insensitive. TRPV2 is required for phagocytic activity of macrophages which are rarely exposed to excessive heat, butwhat activates TRPV2 in vivo remains elusive. Here we describe the molecular mechanism of an oxidation-induced temperature-dependent gating of TRPV2. While high concentrations of H₂O₂ induce a modest sensitization of heat-induced inward currents, the oxidant chloramine-T (ChT), ultraviolet A light, and photosensitizing agents producing reactive oxygen species (ROS) activate and sensitize TRPV2. This oxidation-induced activation also occurs in excised inside-out membrane patches, indicating a direct effect on TRPV2. The reducing agent dithiothreitol (DTT) in combination with methionine sulfoxide reductase partially reverses ChT-induced sensitization, and the substitution of the methionine (M) residuesM528 and M607 to isoleucine almost abolishes oxidation-induced gating of rat TRPV2. Mass spectrometry on purified rat TRPV2 protein confirms oxidation of these residues. Finally, macrophages generate TRPV2-like heat-induced inward currents upon oxidation and exhibit reduced phagocytosis when exposed to the TRP channel inhibitor ruthenium red (RR) or to DTT. In summary, our data reveal a methionine-dependent redox sensitivity of TRPV2 which may be an important endogenous mechanism for regulation of TRPV2 activity and account for its pivotal role for phagocytosis in macrophages.

Magnesium is essential for cellular life, but how it is homeostatically controlled still remains poorly understood. Here, we report that members of CNNM family, which have been controversially implicated in both cellular Mg 2+ influx and efflux, selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. Coexpression of CNNMs with the channel markedly increased uptake of divalent cations, which is prevented by an inactivating mutation to the channel’s pore. Knockout (KO) of TRPM7 in cells or application of the TRPM7 channel inhibitor NS8593 also interfered with CNNM-stimulated divalent cation uptake. Conversely, KO of CNNM3 and CNNM4 in HEK-293 cells significantly reduced TRPM7-mediated divalent cation entry, without affecting TRPM7 protein expression or its cell surface levels. Furthermore, we found that cellular overexpression of phosphatases of regenerating liver (PRLs), known CNNMs binding partners, stimulated TRPM7-dependent divalent cation entry and that CNNMs were required for this activity. Whole-cell electrophysiological recordings demonstrated that deletion of CNNM3 and CNNM4 from HEK-293 cells interfered with heterologously expressed and native TRPM7 channel function. We conclude that CNNMs employ the TRPM7 channel to mediate divalent cation influx and that CNNMs also possess separate TRPM7-independent Mg 2+ efflux activities that contribute to CNNMs’ control of cellular Mg 2+ homeostasis.

The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated. The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms. This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin. ClinicalTrials.gov NCT02712619.

Creatinine is excreted into urine by tubular secretion in addition to glomerular filtration. The purpose of this study was to clarify molecular mechanisms underlying the tubular secretion of creatinine in the human kidney. Transport of [14C]creatinine by human organic ion transporters (SLC22A) was assessed by HEK293 cells expressing hOCT1, hOCT2, hOCT2-A, hOAT1, and hOAT3. Among the organic ion transporters examined, only hOCT2 stimulated creatinine uptake when expressed in HEK293 cells. Creatinine uptake by hOCT2 was dependent on the membrane potential. The Michaelis constant (Km) for creatinine transport by hOCT2 was 4.0 mM, suggesting low affinity. Various cationic drugs including cimetidine and trimethoprim, but not anionic drugs, markedly inhibited creatinine uptake by hOCT2. These results suggest that hOCT2, but not hOCT1, is responsible for the basolateral membrane transport of creatinine in the human kidney.

The organic cation transporters OCT1-3 (SLC22A1-3) facilitate the transport of cationic endo- and xenobiotics and are important mediators of drug distribution and elimination. Their polyspecific nature makes OCTs highly susceptible to drug–drug interactions (DDIs). Currently, screening of OCT inhibitors depends on uptake assays that require labeled substrates to detect transport activity. However, these uptake assays have several limitations. Hence, there is a need to develop novel assays to study OCT activity in a physiological relevant environment without the need to label the substrate. Here, a label-free impedance-based transport assay is established that detects OCT-mediated transport activity and inhibition utilizing the neurotoxin MPP+. Uptake of MPP+ by OCTs induced concentration-dependent changes in cellular impedance that were inhibited by decynium-22, corticosterone, and Tyrosine Kinase inhibitors. OCT-mediated MPP+ transport activity and inhibition were quantified on both OCT1-3 overexpressing cells and HeLa cells endogenously expressing OCT3. Moreover, the method presented here is a valuable tool to identify novel inhibitors and potential DDI partners for MPP+ transporting solute carrier proteins (SLCs) in general.

Key Points The role of transient receptor potential (TRP) channels is best understood in the pain area. As TRP channels are expressed on peripheral nociceptors, where pain is generated, it is hoped that TRP channel blockers will be devoid of the side effects that limit the use of analgesic agents that act on the central nervous system. Several TRP cation channel subfamily V, member 1 (TRPV1) antagonists have advanced to clinical trials, but their side effects (which include hyperthermia and impaired noxious heat detection) have prevented any compounds from progressing beyond Phase II clinical trials. TRPV3 antagonists have shown efficacy in models of neuropathic and inflammatory pain, and one antagonist has entered Phase I clinical trials. An autosomal dominant mutation in the gene that encodes TRP cation channel subfamily A, member 1 (TRPA1) causes familial episodic pain syndrome. Indeed, TRPA1 antagonists have been shown to reduce cold hypersensitivity in rodent models of neuropathic pain without altering normal cold sensation in naive animals. Several TRP channels (such as TRPV1, TRPV4 and TRP cation channel subfamily M, member 8 (TRPM8)) are expressed in the urinary bladder, where they presumably function as sensors of stretch and chemical irritation. TRPV1 and TRPV4 antagonists improve bladder function in rodent models of cystitis. Populations of non-neuronal cells within the skin express many different types of TRP channels that are implicated in the regulation of several key cutaneous functions including skin-derived pruritus, proliferation, differentiation and inflammatory processes. TRPA1 and TRPV1 serve as polymodal sensors in the mammalian respiratory tract that integrate varied inflammatory, oxidant and hazardous irritant stimuli to produce noxious sensations (for example, breathlessness, the urge to cough and nasopharyngeal pain) and respiratory reflexes such as coughing. Several TRP channels — including members of TRP cation channel subfamily C (TRPC) and TRPV — influence the process of gas exchange by regulating airflow, blood flow and airway permeability. Mutations in at least six of the 28 members of the TRP channel superfamily are associated with heritable genetic diseases in humans. These mutations have implicated TRP channels in many pathophysiological states and expanded our understanding of the physiological role of these channels. The role of TRP channels in the brain remains to be elucidated, but it seems to be clear that some members of the superfamily are involved in neuronal excitability and neurotransmitter release. Genetic deletion of TRPC5 leads to an anxiolytic phenotype, whereas a point mutation in TRPC3 leads to ataxia. TRP channels also serve important functions in other diseases that are not fully explored in this Review. For example, cancer and metabolic diseases will be particularly interesting to watch in the future. Transient receptor potential (TRP) channels are a diverse family of cation channels. Here, the authors discuss recent developments in this area, highlight recent developments and setbacks in the field of pain research and analyse TRP channels as targets for skin, pulmonary and urological disorders. Transient receptor potential (TRP) cation channels have been among the most aggressively pursued drug targets over the past few years. Although the initial focus of research was on TRP channels that are expressed by nociceptors, there has been an upsurge in the amount of research that implicates TRP channels in other areas of physiology and pathophysiology, including the skin, bladder and pulmonary systems. In addition, mutations in genes encoding TRP channels are the cause of several inherited diseases that affect a variety of systems including the renal, skeletal and nervous system. This Review focuses on recent developments in the TRP channel-related field, and highlights potential opportunities for therapeutic intervention.