ML 240

ML240 is a potent p97 inhibitor, inhibiting p97 ATPase with IC50 value of 100 nM.

In Vitro:ML240 is a potent p97 inhibitor, with an IC50 of 100 nM. ML240 is active in the UbG76V-GFP stabilization assay (IC50, 0.9 μM). ML240 inhibits p97 competitively with respect to ATP with a Ki values of 0.22 μM. ML240 also inhibits labeling of only three protein kinase domains by >50% when tested at 20 μM: PIP5 K3 (belongs to phosphoinositide-3 kinase family), JAK1 JH2 (N-terminal pseudokinase domain of JAK1), and DNAPK (DNA-dependent protein kinase). ML240 (1.1, 3.3, 10, or 20 μM) induces executioner caspases 3 and 7 and triggers cell death independently of apical caspases 8 and 9[1]. ML240 is cytotoxic to HCT15 and SW403 cells, with GI50s of 0.76 and 0.5 μM after treatment for 24 h, and 0.54 and 0.5 μM after treatment for 72 h, respectively[2].

References:
[1]. Chou TF et al. Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. ChemMedChem, 2013 Feb, 8(2):297-312. [2]. Chou TF, et al. Selective, reversible inhibitors of the AAA ATPase p97. Probe Reports from the NIH Molecular Libraries Program. April 14, 2011.

Prevalence and Characteristics of Exercise-Induced Bronchoconstriction in High School and College Athletes at 2,240 m Altitude.[Pubmed:28239178]

Rev Invest Clin. 2017 Jan-Feb;69(1):20-27.

BACKGROUND: Athletes practicing strenuous physical activities may develop exercise-induced bronchoconstriction (EIB). We aimed to determine the prevalence and features of this condition in Mexico City (altitude, 2,240 m). METHODS: In the present study, 208 high school and college athletes performed a standardized EIB test on a treadmill. RESULTS: Responses to exercise had large between-subject variability in all physiological parameters (forced expiratory volume in one second [FEV1], heart rate, blood oxygen saturation level [SpO2], blood pressure), with nearly similar proportions of subjects in whom FEV1 increased or decreased. According to the recommended cut-off value of 10% FEV1 decrease, only 15 (7.2%) athletes had a positive EIB test. Weight lifters were more prone to develop EIB (three out of seven athletes; p = 0.01). Subjects with a positive EIB test already had a lower baseline forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio (96.4 vs. 103.2% of predicted, respectively; p = 0.047), and developed more respiratory symptoms after exercise than subjects with a negative test. There were no differences with respect to age, gender, body mass index, history of asthma or atopic diseases, smoking habit, and exposure to potential indoor allergens. CONCLUSIONS: The relatively low prevalence of EIB in athletes from Mexico City raises the possibility that high altitude constitutes a protective factor for EIB. In contrast, weight lifters were especially prone to develop EIB, which suggests that repetitive Valsalva maneuvers could be a novel risk factor for EIB. There was a large between-subject variability of all physiological responses to exercise.

Case 240: Meckel Diverticulitis.[Pubmed:28318437]

Radiology. 2017 Apr;283(1):303-307.

History A previously healthy 28-year-old man developed right lower quadrant pain while traveling. The pain progressed over the course of 2-3 days, and his family took him to a local emergency department. He was found to have an elevated white blood cell count of 12.2 x 10(9)/L (reference range, [3.9-10.3] x 10(9)/L), with a predominance of neutrophils. Contrast material-enhanced computed tomography (CT) of the abdomen and pelvis was performed, and findings were abnormal. The patient elected to leave the emergency department without undergoing treatment, and he returned home via airplane. He presented to his primary care physician for further evaluation later that same day. His physician noted a mildly distended abdomen that was diffusely tender on palpation, with rebound tenderness in the right lower quadrant. The patient was admitted to our hospital, and the general surgery department was consulted. The CT images that were obtained at the outside institution were submitted to our radiology department for interpretation.

Surface-dominated conduction up to 240 K in the Kondo insulator SmB6 under strain.[Pubmed:28369051]

Nat Mater. 2017 Jul;16(7):708-711.

SmB6 is a strongly correlated mixed-valence Kondo insulator with a newly discovered surface state, proposed to be of non-trivial topological origin. However, the surface state dominates electrical conduction only below T( *) approximately 4 K (ref. ), limiting its scientific investigation and device application. Here, we report the enhancement of T( *) in SmB6 under the application of tensile strain. With 0.7% tensile strain we report surface-dominated conduction at up to a temperature of 240 K, persisting even after the strain has been removed. This can be explained in the framework of strain-tuned temporal and spatial fluctuations of f-electron configurations, which might be generally applied to other mixed-valence materials. We note that this amount of strain can be induced in epitaxial SmB6 films via substrate in potential device applications.

Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase.[Pubmed:23316025]

ChemMedChem. 2013 Feb;8(2):297-312.

To discover more potent p97 inhibitors, we carried out a structure-activity relationship study of the quinazoline scaffold previously identified from our HTS campaigns. Two improved inhibitors, ML240 and ML241, inhibit p97 ATPase with IC(50) values of 100 nM. Both compounds inhibited degradation of a p97-dependent but not a p97-independent proteasome substrate in a dual-reporter cell line. They also impaired the endoplasmic-reticulum-associated degradation (ERAD) pathway. Unexpectedly, ML240 potently stimulated accumulation of LC3-II within minutes, inhibited cancer cell growth, and rapidly mobilized the executioner caspases 3 and 7, whereas ML241 did not. The behavior of ML240 suggests that disruption of the protein homeostasis function of p97 leads to more rapid activation of apoptosis than is observed with a proteasome inhibitor. Further characterization revealed that ML240 has broad antiproliferative activity toward the NCI-60 panel of cancer cell lines, but slightly lower activity toward normal cells. ML240 also synergizes with the proteasome inhibitor MG132 to kill multiple colon cancer cell lines. Meanwhile, both probes have low off-target activity toward a panel of protein kinases and central nervous system targets. Our results nominate ML240 as a promising starting point for the development of a novel agent for the chemotherapy of cancer, and provide a rationale for developing pathway-specific p97 inhibitors.