Changes in fractional exhaled nitric oxide, forced expiratory volume in one second, and forced oscillation technique parameters over three years in adults with bronchial asthma managed under Yokohama Seibu Hospital's coordinated care system.

BACKGROUND: In western Yokohama, our hospital and primary care clinics manage adults with asthma via a coordinated care system. We investigated the changes in the fractional expired nitric oxide (FeNO), forced expiratory volume in 1 second (FEV1), and forced oscillation technique (FOT) parameters over 3 years in a cohort of patients in our collaborative system. METHODS: From 288 adults with well controlled asthma managed under the Yokohama Seibu Hospital coordinated care system between January 2009 and May 2018, we selected 99 subjects to undergo spirometry, FeNO and FOT testing over 3 years and analyzed the changes in these parameters. RESULTS: Of the 99 patients enrolled, 17 (17.2%) experienced at least one exacerbation (insufficiently controlled (IC)), whereas, 82 (82.8%) remained in well controlled during the 3-year study period. Of well-controlled patients, 54 patients (54.5%) met the criteria for clinical remission under treatment (CR); the remaining 28 patients did not meet the CR criteria (WC). There were no differences in FeNO, FEV1, or FOT parameters at baseline among the IC, WC, and CR groups. The levels of FEV1 decreased gradually, whereas the levels of FeNO decreased significantly over 3 years. The levels of percent predicted FEV1 (%FEV1) significantly increased. We also observed significant improvement in FOT parameters; reactance at 5 Hz (R5), resonant frequency (Fres), and integral of reactance up to the resonant frequency (AX). The CR group demonstrated significant relationships between the change in FeNO and the change in FEV1 and between the change in FEV1 and the change in FOT parameters. No significant correlations emerged in the IC or WC group. CONCLUSION: The decrease in FeNO and increase in %FEV1, we observed in all study participants suggest that the coordinated care system model benefits patients with asthma. Although it is difficult to predict at baseline which patients will experience an exacerbation, monitoring changes in FeNO and FEV1 is useful in managing patients with asthma. Furthermore, monitoring changes in R5, Fres, and AX via forced oscillation technique testing is useful for detecting airflow limitation.

[THE RELATIONSHIP AMONG BRONCHIAL HYPERSENSITIVITY, BRONCHIAL HYPER REACTIVITY, AND BRONCHIAL HYPERRESPONSIVENESS IN ASTOGRAPH].

BACKGROUND: Bronchial hyperresponsiveness testing is useful for diagnosing and predicting the risk of bronchial asthma attacks. The Astograph is a tidal breathing method often used in as bronchial provocation testing in Japan. The minimum methachorine dose (Dmin) indicates bronchial sensitivity and is used mainly as an index of bronchial hyperresponsiveness. However, Dmin does not measured hyperresponsiveness, it cannot be compared directly with PC20 in standard methods using FEV1. METHODS: We investigated the relationship among sensitivity, reactivity, and hyperresponsiveness with the Astograph. We recruited 142 patients with confirmed or suspected bronchial asthma from outpatient clinic at St. Marianna University School of Medicine, Yokohama City Seibu Hospital. We calculated Dmin, SGrs/Grscont, PD35Grs, and PD15Grs compared them as bronchial hyperresponsiveness indices. RESULTS: Subjects had suspected asthma (n=103), or required assessment of asthma remission (n=39). There were significant relationships between logDmin and logPD35Grs (r=0.838, p<0.001), and between parameters and SGrs/Grscont (log PD35Grs r=-0.504, p<0.001, strong, logDmin: r=-0.191, p=0.023, weaker). Among subjects positive for hypersensitivity, (Dmin<10), 38 (36.5%) showed negative hyperresponsiveness (PD35Grs>25). PD15Grs was a strongly and significantly correlated with Dmin and PD35Grs. The ROC curve to detect PD35Grs<25, showed that the cutoff of PD15Grs was 10.7 (AUC 0.983, sensitivity 0.984, specificity 0.905). CONCLUSION: In Astograph, evaluation of bronchial hyperresponsiveness, we focused on relationship differences between sensitivity and reactivity, and hyperresponsiveness. We revealed the usefulness of the PD15Grs evaluation method.

[THE INFLUENCE OF SENSITIZATION TO ASPERGILLUS AND ALTERNARIA IN ADULT BRONCHIAL ASTHMATICS MANAGED VIA YOKOHAMA CITY SEIBU HOSPITAL'S COORDINATED-CARE SYSTEM].

BACKGROUND: The sensitizations to various fungal allergens influence to exacerbation of bronchial asthma. Aspergillus (Asp) and Alternaria (Alt) were one of important fungal allergens for asthma. AIM AND METHODS: To investigate the influence of sensitization to Asp or Alt in adult asthmatics managed via our asthma coordinated-care system, we recruited 119 patients (91 women) who were measured IgE for Asp (IgE-Asp) and IgE for Alt (IgE-Alt) at three times during two years,Results: In 119 patients, we detected positive IgE for Asp (IgE-Asp(+)) in 19 patients and positive IgE for Alt (IgE-Alt(+)) in 11 patients. 9 patients showed positive both of them. During two years, 7 patients became positive IgE-Asp and 3 cases became negative. And also, 3 cases became positive IgE-Alt and 3 cases became negative. At baseline, serum IgE, IgG4, and inhaled corticosteroid (ICS) dose of the group with IgE-Asp (+) or IgE-Alt (+), were significant higher than those of negative group. Among three groups, there was no significant change about other parameters at baseline, exacerbation frequency, or the change of parameters during two years. CONCLUSION: The sensitizations to Asp or Alt were present in 19 asthmatics (16%) managed via our coordinate-care system. During 2 years, there was not significant change at exacerbation frequency among three groups, but the levels of IgE, IgG4, or ICS dose were significantly higher at IgE-Asp (+) or IgE-Alt (+) group than negative group. In the asthma management, it was considered necessary to pay attention to the sensitization to Asp or Alt.

[A RESEARCH OF ADULT BRONCHIAL ASTHMATICS MANAGED UNDER YOKOHAMA CITY SEIBU HOSPITAL'S COORDINATED-CARE SYSTEM].

BACKGROUND: Our hospital in the western part of Yokohama City managed adult bronchial asthma patients via a coordinated care system with primary care clinics. The aim of the system is to provide effective daily and emergency medical care. METHODS: The study comprised 288 adult stable asthmatics (201 women) who were examined at Yokohama City Seibu Hospital between Jan 2009 and May 2018 and who were being managed under our coordinated care system at one of 80 primary clinics or hospitals. RESULTS: Of the 288 patients enrolled, 188 continued, 37 ended under management, and 63 dropped out from this system. The drop-out rate was highest at visit 1 (9%). The main reasons for end of cooperation under management were readjustment of asthma treatment and treatment for other diseases. The reasons for dropping out were low adherence, older age, and mild symptoms. There was a significant tendency in the frequency of patients who continued, ended under management, or dropped out (x2: 26.053, p=0.016), and the drop-out rate was significantly higher at visit 1. Comparing the characteristics of the patients who continued, ended under management, and dropped out within two visit, those who had dropped out were significantly younger (p=0.0067) and their duration of asthma was shorter (p=0.0009). The frequencies of emergency department visit and hospitalization were high until visit 2, but no significant trends were observed. CONCLUSION: Our coordinated care system managed 188 asthmatic patients (65.2%) properly. Patients with low adherence tended to drop out from the system at visit 1.

The relationship between peak inspiratory flow and hand grip strength measurement in men with mild chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) decreases quality of life and muscular strength. Inspiratory flow is important for inhalants in the bronchi but is complicated to measure in routine practice. We hypothesized that hand grip strength (HGS) would correlate with inhalation rate in patients with mild COPD. METHODS: The COPD patients were recruited at the St. Marianna University School of Medicine, Yokohama Seibu Hospital, from 2015 to 2018. We measured peak inspiratory flow (PIF) through an In-Check flow meter attached with Diskus [PIF(D)] and Turbuhaler [PIF(T)] inhalers. The 6-min walking test (6MWT), and the fraction of exhaled nitric oxide (FENO), spirometry, HGS, or forced oscillation technique (FOT) parameters were measured. RESULTS: Forty-four subjects were enrolled. All were men, with a mean age (± SD) of 77.8 ± 9.36 years. Thirty-nine patients had mild COPD. PIF(D) was 110 (80, 140) L/min (median, interquartile range), PIF(T) was 80 (70, 90) L/min, and HGS was 28.7 (13.8, 43.6) kgf. PIF(D) and PIF(T) were significantly correlated (r = 0.443, p = 0.003). PIF(D) was significantly correlated with age (r = - 0.327, p = 0.030) and HGS (r = 0.326, p = 0.031). PIF(T) was significantly correlated with age (r = - 0.328, p = 0.030), FVC (r = 0.351, p = 0.019), 6MWT distance (r = 0.392, p = 0.011), and HGS (r = 0.328, p = 0.030). CONCLUSION: HGS might be more useful for predicting PIF than other parameters. Also, elderly COPD patients need to be taught inhaled methods carefully.

Pleurodesis After Bronchial Occlusion for Inoperable Secondary Spontaneous Pneumothorax.

BACKGROUND: In many cases of secondary spontaneous pneumothorax (SSP), surgery is not feasible. Furthermore, in cases with a collapsed lung or numerous air leaks, pleurodesis is ineffective, and treatment options are severely limited. For these cases, bronchial occlusion might be the only effective treatment, despite the low success rate. If, however, bronchial occlusion can expand the lung and reduce air leakage, it can positively amplify later effects on pleurodesis, resulting in a powerful treatment. We reviewed the clinical data of patients who underwent bronchial occlusion with endobronchial Watanabe spigot (BO-EWS) and pleurodesis to investigate the usefulness of bronchial occlusion therapy in inoperable SSP patients. MATERIALS AND METHODS: This single-center, retrospective study reviewed 36 cases of inoperable SSP patients who underwent pleurodesis after BO-EWS from April 2007 to October 2018. Twenty cases were allocated to the air leak analysis group, and 16 cases were included in the pneumothorax volume analysis group. The Robert David Cerfolio classification and the Collins method were used to evaluate air leak and pneumothorax volume, respectively. RESULTS: Pneumothorax volumes decreased significantly after BO-EWS from 29.1%±17.3% to 12.1%±8.8%, while the air leak score decreased from 2.9±1.4 to 1.2±1.0. The success rate for chest tube removals in cases that underwent pleurodesis after BO-EWS was 85.0% (17/20). CONCLUSIONS: This study demonstrated the synergistic effectiveness of BO-EWS and the usefulness of pleurodesis treatment in inoperable SSP patients with lung collapse or numerous air leaks. We believe that this treatment will benefit patients with inoperable SSP which, until now, has had few treatment options.

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors.

The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.

TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia.

TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.

[CHARACTERISTICS OF ADULT ASTHMATICS COMPLICATED WITH PULMONARY THROMBOEMBOLISM IN YOKOHAMA CITY SEIBU HOSPITAL].

BACKGROUND: Evidences have shown that bronchial asthma (BA) enhances the risk of pulmonary thromboembolism (PTE). We previously reported the cases of adult BA patients complicated with PTE. (Aim) To clarify the risk factors of PTE in BA patients, we investigated about the characteristics and risk of contrast medium about patients coexisting asthma and PTE. METHODS: We investigated adult asthmatics who visited our hospital and examined chest contrasted CT from January 2011 to 2018.March, retrospectively. RESULTS: Fifty seven times examinations (33 asthmatics) were detected from 304 times of enhanced chest CT. We examined twenty times enhanced CT without premedication, but no subjects had side effect such as asthma attack. And also, we diagnosed 12 asthmatics as PTE from 33 patients. The subjects with PTE were high BMI (p=0.024) heavy weight (p=0.033), compared with asthmatics without PTE. There were no significant changes about lung function test, smoking history, sex and the levels of D-dimer among two groups. CONCLUSION: Adult asthmatics with PTE were high BMI and heavy compared with those without PTE.

Relationships among bronchodilator reversibility, the fraction of exhaled nitric oxide, and the parameters of the forced oscillation technique in adult asthma treated with inhaled corticosteroids and long-acting ß2 agonists combination.

In bronchial asthma, both airway inflammation and reversible airway narrowing require assessment and treatment. These two pathologies are treated primarily with inhaled corticosteroids (ICS) and long-acting ß2 agonists (LABA), respectively. Therefore, ICS-LABA combinations are widely used to treat asthma. Airway inflammation and reversible airway narrowing are assessed primarily with fraction of exhaled nitric oxide (FENO) and bronchodilator reversibility (BDR). The forced oscillation technique (FOT) has recently attracted attention as a method for assessing obstructive respiratory disturbance. However, little is known about the relationships among these assessments. Therefore, we investigated the relationships among BDR, FENO, and FOT during ICS-LABA combination therapy. The subjects comprised 87 patients (25 men and 62 women) with asthma undergoing ICS/LABA combination therapy from July to September 2017. We applied the FENO test, FOT, and BDR testing without the patients stopping their therapy. The rates of change in FEV1 (ΔFEV1%) was correlated with FENO (r = 0.278). Among the FOT parameters, X5 (r = -0.263), Fres (r = 0.292), and AX (r = 0.245) were significantly correlated with ΔFEV1%. FENO, Fres and %FEV1 at baseline in these stable asthmatics were significantly assosiated with ΔFEV1% independently of the effects of age, atopy and body mass index (BMI). These results suggest that FENO and the results of respiratory function testing and FOT reflect different aspects of asthma and should be combined and comprehensively evaluated.

Activity of TAS4464, a novel NEDD8 activating enzyme E1 inhibitor, against multiple myeloma via inactivation of nuclear factor κB pathways.

The ubiquitin proteasome pathway is essential for the proliferation and survival of multiple myeloma (MM) cells. TAS4464, a novel highly potent inhibitor of NEDD8 activating enzyme, selectively inactivates cullin-RING ubiquitin E3 ligases, resulting in accumulation of their substrates. Here, we examined 14 MM cell lines treated with TAS4464. TAS4464 induced growth arrest and cell death in the MM cell lines even in the presence of bone marrow stromal cells. It also induced the accumulation of phospho-inhibitor of κBα and phospho-p100, impaired the activities of nuclear factor κB (NF-κB) transcription factors p65 and RelB, and decreased the expression of NF-κB target genes, suggesting that TAS4464 inhibits both the canonical and non-canonical NF-κB pathways. TAS4464 had similar effects in an in vivo human-MM xenograft mouse model in which it was also observed to have strong antitumor effects. TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab and elotuzumab. Together, these results suggest that the anti-MM activity of TAS4464 occurs via inhibition of the NF-κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies.

TAS4464, A Highly Potent and Selective Inhibitor of NEDD8-Activating Enzyme, Suppresses Neddylation and Shows Antitumor Activity in Diverse Cancer Models.

NEDD8-activating enzyme (NAE) is an essential E1 enzyme of the NEDD8 conjugation (neddylation) pathway, which controls cancer cell growth and survival through activation of cullin-RING ubiquitin ligase complexes (CRL). In this study, we describe the preclinical profile of a novel, highly potent, and selective NAE inhibitor, TAS4464. TAS4464 selectively inhibited NAE relative to the other E1s UAE and SAE. TAS4464 treatment inhibited cullin neddylation and subsequently induced the accumulation of CRL substrates such as CDT1, p27, and phosphorylated IκBα in human cancer cell lines. TAS4464 showed greater inhibitory effects than those of the known NAE inhibitor MLN4924 both in enzyme assay and in cells. Cytotoxicity profiling revealed that TAS4464 is highly potent with widespread antiproliferative activity not only for cancer cell lines, but also patient-derived tumor cells. TAS4464 showed prolonged target inhibition in human tumor xenograft mouse models; weekly or twice a week TAS4464 administration led to prominent antitumor activity in multiple human tumor xenograft mouse models including both hematologic and solid tumors without marked weight loss. As a conclusion, TAS4464 is the most potent and highly selective NAE inhibitor reported to date, showing superior antitumor activity with prolonged target inhibition. It is, therefore, a promising agent for the treatment of a variety of tumors including both hematologic and solid tumors. These results support the clinical evaluation of TAS4464 in hematologic and solid tumors.

[A CASE OF BRONCHIAL ASTHMA ASSOCIATED WITH BRONCHIOLAR EOSINOPHILIA AND TREATED WITH MEPOLIZUMAB].

A 68 year-old woman with dyspnea and cough had been treated with inhaled corticosteroids for X-15 years, but her symptoms worsened in X year. High-resolution chest CT revealed small centrilobular nodules in the right upper lobe in March X year. The patient was diagnosed with asthma and diffuse panbronchiolitis and treated with inhaled corticosteroids, a long-acting beta agonist, and clarithromycin, but her condition did not improve and her peripheral blood eosinophil count increased. In August X year, we performed a transbronchial biopsy of the right upper lung. Histopathological examination revealed eosinophilia in the bronchial secretions and mild nonspecific inflammatory changes. The diagnosis was bronchial asthma associated with bronchiolitis. The patient was treated successfully with mepolizumab.

Discovery of 3-Ethyl-4-(3-isopropyl-4-(4-(1-methyl-1 H-pyrazol-4-yl)-1 H-imidazol-1-yl)-1 H-pyrazolo[3,4- b]pyridin-1-yl)benzamide (TAS-116) as a Potent, Selective, and Orally Available HSP90 Inhibitor.

The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth, and survival. A novel series of HSP90 inhibitors were discovered by structure-activity relationship (SAR)-based optimization of an initial hit compound 11a having a 4-(4-(quinolin-3-yl)-1 H-indol-1-yl)benzamide structure. The pyrazolo[3,4- b]pyridine derivative, 16e (TAS-116), is a selective inhibitor of HSP90α and HSP90ß among the HSP90 family proteins and exhibits oral availability in mice. The X-ray cocrystal structure of the 16e analogue 16d demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of 16e demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant body weight loss.

Pulmonary Perfusion Using Intrabronchial Capnography in Pulmonary Artery Stenosis.

Stenting at the flow-limiting segment can improve the ventilation-perfusion ratio in patients with central airway stenosis. However, there is no quantitative examination for assessing the perfusion status during interventional bronchoscopy. Intrabronchial capnography can estimate regional gas exchange by measuring carbon dioxide concentration. We herein report a case of bilateral bronchial stenosis where stenting was able to improve ventilation-perfusion ratio using intrabronchial capnography. A 44-year-old man was admitted to our institution with orthopnea. Chest computed tomography showed an extrinsic compression at the bilateral main bronchus and right pulmonary artery due to a mediastinal mass. After introduction of general anesthesia, arterial oxygen tension suddenly decreased in the supine position. After initial stenting, an increase was seen in ventilation at the right lung; however, a ventilation-perfusion mismatch occurred due to an increase in dead-space ventilation at the right pulmonary artery stenosis. Intrabronchial capnography was an effective modality to confirm the regional perfusion status during interventional bronchoscopy in real time.

A Novel Technique for the Placement of Endobronchial Watanabe Spigots Into the Bronchus: Side-Grasping Method.

BACKGROUND: Bronchial occlusion with an endobronchial Watanabe spigot (EWS) is effective for the management of persistent pulmonary air leaks; however, an optimal procedure for placing the spigot at the target bronchus remains debatable. The procedure most currently applied involves grasping the middle of the graspable part of the EWS with grasping forceps (conventional method). In this study, we assess a new technique, the side-grasping method, to maneuver the spigot into the target bronchus by using rotatable biopsy forceps to grasp the edge of the graspable part of the EWS. The aim of this study is to evaluate the effectiveness of this new technique for the simple placement of the EWS. METHODS: To compare the number of bronchoscopists who were able to place the EWS correctly within 10 minutes, and the time needed to place each spigot for both methods into 4 canine bronchi. RESULTS: More bronchoscopists correctly placed the EWS within 10 minutes using the side-grasping method compared with the conventional method (35/40 vs. 15/40, P<0.01). The total time needed to place spigots into all bronchi using the side-grasping method was 13±2.2 minutes versus 27.8±3.6 minutes using the conventional method (P<0.01). CONCLUSION: The side-grasping method described in this study was a simple and effective technique for correctly placing an EWS spigot into the target bronchus.

Intractable pneumothorax managed by talc pleurodesis and bronchial occlusion with spigots.

Three cases of inoperable secondary spontaneous pneumothorax were diagnosed in patients with chronic obstructive pulmonary disease. Two cases initially underwent bronchial occlusion with endobronchial Watanabe spigot (EWS), while one underwent talc poudrage with pleuroscopy. As air leaks were not stopped completely in all cases with the initial procedures, we performed additional interventional treatments: pleuroscopic talc poudrage in cases when bronchial occlusion was performed first; and bronchial occlusion with EWS for a case that initially underwent talc pleurodesis. The air leaks ceased in all cases without complication. We successfully removed chest tubes 2-10 days after secondary procedure, which was 10-23 days after the first procedure. The combination of talc pleurodesis and bronchial occlusion with EWS, when a single, initial interventional treatment fails, can be considered in cases of intractable, inoperable secondary pneumothorax.

TAS-116, a highly selective inhibitor of heat shock protein 90α and ß, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models.

The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo[3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90α and ß that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90α and ß alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.