ライフサイエンスコーパス: hit

1 (50 compounds) identified approximately 100 hits and four distinct chemotypes, the most promising of

2 Subjecting approximately 100 hits to Perturb-seq enabled high-precision functional cl

3 The screening led to 115 hits for which we determined biochemical IC50, thus iden

4 e associated with PH-HFpEF, we developed a 2-hit PH-HFpEF model in rats with multiple features of met

5 ological activity in vitro, we identified 21 hit compounds which inhibited IMPalpha/beta1:C binding w

6 Unusually, the top 3 hits all contained stop codons in the randomized region

7 irtual screening campaign yielded a high 32% hit rate, identifying novel fragment-like and lead-like

8 brary of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic n

9 Transcriptome profiling revealed 349 hits with a 2-fold expression difference threshold (217

10 ssibility for chemical synthesis, out of 593 hits, 39 were left top hits.

11 This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modula

12 ounds) identified a further approximately 90 hits across three quinolone subtemplates.

13 The pyrrolopyrimidine AEE788 (a hit for anti-HAT drug discovery) associates with three t

14 , for which we obtain novel chemotypes and a hit rate that approaches 40%.

15 aluated by consensus virtual screening and a hit was identified.

16 thiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of h

17 One of them was selected as a hit and optimized by a structure-activity relationship a

18 repeating unit (RU) of ST2 CPS, emerged as a hit from the glycan array screens.

19 We now describe a hit-to-lead effort resulting in the discovery of a poten

20 in, we report the optimization process for a hit compound that has emerged from a phenotypic screen r

21 This identified a hit that subsequent in vitro analysis showed directly bi

22 anger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS).

23 confined subsets of PAINS produced abundant hits.

24 ide evidence that maternal immune activation hits a key neurodevelopmental process, the excitatory-to

25 f the coinhibitory molecule PD-1, additional hits are required.

26 e than 100 compounds and revealed additional hits and temporal profiles in good correlation with repo

27 On the basis of a Weinreb amide hit compound, we designed and synthesized a diverse set

28 Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic s

29 tional strategies for fragment screening and hit-to-lead development.

30 erefore represent promising antischistosomal hits for further hit-to-lead optimization.

31 in cell cycle regulation, were identified as hits in four different RNAi screens and we therefore stu

32 Flavonols were identified as hits, and a library of 16 derivatives was synthesized.

33 et of genes or nucleotide locations, such as hits from an association study.

34 cer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Gl

35 These profiles allow teams to quickly assess hit series for desirable ADMET properties or suspected l

36 reet lighting-other drivers can better avoid hitting them, directly reducing the accident rate.

37 The combination of structure-based hit identification and subsequent optimization of the ce

38 egions) and farmers in these regions will be hit hardest by increasing temperatures.

39 t our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and pro

40 nally, compound P-902 was identified as best hit.

41 An analysis of reciprocal best hits shows that 31 genes are conserved between African s

42 0,842 assembled transcripts and 30,518 BLAST hits.

43 hologues computed from reciprocal best BLAST hits or OrthoMCL, and DAGchainer, and outputs an overvie

44 s faster than a popular artificial centering hit-and-run algorithm, enabling reliable and tractable s

45 We reported finding zero common hits in the intersection of these four comparisons.

46 creening of candidates returned 14 confirmed hits with activities in the nano- to low-micromolar rang

47 tion of a new sampling algorithm, coordinate hit-and-run with rounding (CHRR).

48 Greece was one of the countries hit the hardest by the 2008 financial crisis in Europe.

49 Both noncovalent and covalent hits emerge from such endeavors.

50 f SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease.

51 od is that the contribution of each database hit to the taxonomic assignment of the query sequence is

52 egree of sequence similarity of the database hit to the query sequence.

53 ilarity between query sequences and database hits using pairwise sequence alignment.

54 lowest common ancestors of multiple database hits for each query sequence, and further classification

55 tein target is a key component when defining hit-finding strategies or when prioritize among drug tar

56 applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding k

57 ips around one of those previously described hits, NSC 60339 (1).

58 Double-hit lymphomas may arise as a consequence of the transfor

59 his hemisphere as a consequence of a "double-hit" phenomenon because of preexisting alterations in co

60 ay constitute an attractive novel and double-hit approach for the treatment of atherosclerosis.

61 ll lymphoma, have been referred to as double-hit lymphomas (or triple-hit lymphomas if all 3 rearrang

62 slocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of c

63 nd/or BCL6 rearrangements, so-called "double-hit" lymphomas (HGBL-DH), are aggressive lymphomas that

64 re no published prospective trials in double-hit lymphoma, however retrospective studies strongly sug

65 Surprisingly, under conditions of LPS double-hit an interference of a postulated alpha7nAChR - ferrop

66 ch to the evaluation and treatment of double-hit lymphoma, with an eye toward future clinical trials

67 Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DEL

68 These double-hit lymphomas may have arisen from a tumor precursor tha

69 Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival fol

70 Patients with double-hit lymphomas have a poor prognosis when treated with st

71 ening hits limits our understanding of early hit compounds.

72 To assess their applications in the EED hit-to-lead optimization process, large amount of thermo

73 algorithm is based on the provably efficient hit-and-run random walk and crucially uses a preprocessi

74 Highly efficient hits (LE > 0.6) often result.

75 Enhancing hits and generating false alarms both scaled with stimul

76 n human and rabbit sera and identify epitope hits.

77 to be inactive in 50 or more assays, exhibit hit rates that are comparable to those of compounds test

78 gh-throughput screening paradigm facilitated hit identification, while structure-based design and mul

79 duce lung injury in the presence of a "first hit" in humans (Dutch Trial Register: NTR4455).

80 and early progenitor clones with the "first hit" mutation in APC that subsequently gave rise to both

81 tubal epithelial cells (serving as the first hit) - into pathogenic fibrosis.

82 astic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leuk

83 w overall, with median values of two to five hits for PAINS tested in hundreds of assays.

84 al models such as Caenorhabditis elegans for hit identification and lead optimization.

85 ing kinetic and thermodynamic parameters for hit selection.

86 eming them as a promising starting point for hit-to-lead development.

87 idine carboxamide series was prioritized for hit to lead optimization.

88 els to generate in silico ADMET profiles for hit series to enable more complete characterizations of

89 gene expression data, optimal thresholds for hit selection and network/pathway analysis.

90 ated and utilized as complementary tools for hit and lead optimizations in drug discovery.

91 Four hits were tricyclic antidepressants (TCAs), and they rep

92 Fourteen hits showed increased activity (improved >4.5-fold in ly

93 Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors

94 l structure of caspase-7 bound to a fragment hit and a thorough kinetic characterization of a zymogen

95 We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD

96 e in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic p

97 of crystallographically intractable fragment hits into more potent binders.

98 probing the SAR around one or more fragment hits.

99 , selected on the basis of previous fragment hits.

100 We show that fragment hits can be advanced to furnish selective ligands that a

101 promising antischistosomal hits for further hit-to-lead optimization.

102 chment for an inputted list of genes (e.g., 'hits' from a screen) and search for additional genes wit

103 n and the requirement for additional genetic hits remain unclear.

104 We suggest that multiple genetic hits may act in combination to degrade lysosomal functio

105 y to overt disease requires multiple genetic hits.

106 me-wide association studies revealed 28 GWAS hits in potential candidate genes likely to affect trait

107 Several of these hub genes are GWAS hits for traits that might involve dysfunction of brain

108 s provide great supporting evidence for GWAS hits and important insights into the regulatory pathways

109 Given that most GWAS hits are in putative regulatory regions and transcript a

110 and discovered an aryloxazole-based anti-HCV hit.

111 Seed alignments, profile HMMs, hit lists and other underlying data are available for do

112 Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has bee

113 imization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated

114 biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bi

115 Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compoun

116 a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leuk

117 ry of 107 FDA-approved compounds to identify hits that prevented the age-dependent functional deterio

118 sults from the 2015 contest show an improved hit rate when compared to results from the 2014 contest.

119 NMR binding assays are routinely applied in hit finding and validation during early stages of drug d

120 ilitate the triage of candidate compounds in hit-to-lead campaigns.

121 Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-p

122 rein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-(

123 ationships from identification of an initial hit in a high-throughput screen through selection of taz

124 report the discovery of a promising initial hit compound targeting the Fanconi anemia ubiquitin-conj

125 ined the TAR binding affinity of the initial hit and displaced a Tat-derived peptide with an IC50 of

126 ther 70 compounds that comprised the initial hit chemotypes were subsequently sourced from the full C

127 positives that permeate the pool of initial hits.

128 from the SAR exploration around the initial hits, the optimization process focused on the improvemen

129 ategy, allowing the generation of innovative hits/leads and successful optimization processes.

130 -cell RNA sequencing (RNA-seq) technology is hitting its stride and is beginning to be widely adopted

131 LCL hits were enriched for EBV-induced genes, including vira

132 Our lead hit, JMJD6, mediates the upregulation of in vivo stress

133 cused on validating endosome/Golgi-localized hits specific for STx2 and found that depletion of UNC50

134 ore or less optimal regime to end with a low hit rate after satiation.

135 t a concentration of 10 muM, there were many hits for JJC8-016, binding affinities in the range of it

136 ng the HSQC spectrum, and the top metabolite hits are then validated against the TOCSY-type experimen

137 ene RANBP1, were evaluated for "second mGluR hits".

138 y in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment librar

139 matosis are defined by distinctive molecular hits.

140 These small-molecule hits demonstrated balanced activities at the targets, mo

141 argeting or replacement as a realistic multi-hit, therapeutic strategy for AD.

142 e Markov chain models that capture the multi-hit initiation-promotion-malignant-conversion hypothesis

143 ing clinical outcomes in patients with multi-hit injuries.

144 We also searched for potential "multiple-hit" cases; one proband carried a rare AUTS2 variant in

145 A series of additional mutational hits (2nd Hit) transforms the expanding clone into cance

146 ed on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone

147 viewing LIP-associated autoimmunity as an n-hit model, we suggest a more quantitative view of lympho

148 tion of organoarsenical leads of the natural hit molecule.

149 each year, and just 7% of shallows were not hit.

150 cted VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC

151 uberculosis (Mtb) in order to identify novel hits with antitubercular activity.

152 Instruction compliance (R-hits minus NR-hits) was significantly related to negative coupling bet

153 It can obtain hits within a single day while consuming minimal amounts

154 t challenges remain in the prioritization of hit series.

155 ion and profoundly impact the progression of hit series.

156 fatal accidents, it did decrease the rate of hit and run accidents, suggesting that the policy reduce

157 ng sites and optimization of interactions of hits using the structure of the target protein.

158 cidation of the mechanism of action (MoA) of hits from these noisy high-throughput screens remain dif

159 lly and can enable efficient optimization of hits to potent leads.

160 ompounds, and generates a high percentage of hits.

161 ponsible for disproportionate percentages of hits but are false actives.

162 and analyzing the effects of off targets on hit calling.

163 stance mechanism of M. smegmatis against one hit, 3-bromo-N-(5-nitrothiazol-2-yl)-4-propoxybenzamide

164 a collection of beta-lactones, we found one hit with potent anti-mycobacterial and bactericidal acti

165 oic acid (WTA) inhibitors, we identified one hit, which was expanded through chemical synthesis into

166 proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in c

167 stematic series of analogues of the original hit using a structure-based drug design strategy, which

168 present, per se or in association with other hits, a risk factor for developing psychotic-like sympto

169 ductase 1 (NQO1) was the top oxidoreductase "hit".

170 of our first neuroprotective brain penetrant hit compound MPAQ (5c).

171 derivative, was characterized as a positive hit.

172 vage events can be a cause of false positive hit identification.

173 T interaction domain identified one positive hit compound and two analogs of the hit with high cytoto

174 sterase activity and identified 714 positive hits.

175 shunt that greatly minimizes false-positive hits, we identify mitoxantrone out of more than 600 clin

176 multitude of data, including false-positive hits.

177 d screening in the context of false-positive hits.

178 ositives by selectively identifying positive hits exclusively when a ligand at the binding site of in

179 ld benefit from an easy way to mark positive hits.

180 Compound 3i is a potent hit (TBK1 DC50 = 12 nM, Dmax = 96%) with excellent selec

181 obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 muM) in complex with the en

182 The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phen

183 en against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in

184 ss this concern, here we developed a potent "hit" compound, VSP-51, which is a novel selective PPARga

185 al and approved drugs): 28% of the predicted hits were reported in literature as ligands of SULT1E1.

186 system, was identified as the most promising hit.

187 f dose-response curves of the most promising hits.

188 reening has identified a number of promising hits.

189 m a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomai

190 The initial pyrrolidine hit was modified by moving the position of the carboxyli

191 Instruction compliance (R-hits minus NR-hits) was significantly related to negativ

192 In good memory performers (R-hits minus false alarm), the coupling was stronger in R

193 Human homologs of top-ranked hits protected against alphaSyn-induced cell death in a

194 of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-iso

195 However, oftentimes, picking relevant hits from such screens and generating testable hypothese

196 From the remaining hits, a selection of nine molecules was subjected to bio

197 nt improvement over our previously reported "hit" NC9.

198 Retrieved hits were screened for inclusion and were evaluated with

199 etylase activity, scored as a significant SB hit.

200 to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues wit

201 sp(3) character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM s

202 ic inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5,

203 d optimization, a 5 microM virtual screening hit was transformed to a series of very potent nanomolar

204 rcity of historical ADMET data for screening hits limits our understanding of early hit compounds.

205 SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C

206 more ring structures dominated the screening hits, including nitroaromatic compounds that induce subs

207 The molecular combination of these screening hits led to compound 22a (PF-543) with 2 orders of magni

208 and altered DNA methylation may be a second hit contributing to penetrance.

209 e gastrointestinal C. muridarum, as a second hit, to transmucosally convert tubal repairing - initiat

210 dren with syndromic ASD and if mGluR "second hit" confers additional risk for ASD in 22q11.2 Deletion

211 fy additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression.

212 eles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed.

213 set of the offspring also received a second 'hit' of lipopolysaccharide (LPS), which simulates a bact

214 ed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflam

215 c instability, eventually allowing secondary hits in the genome that promote tumorigenesis.

216 discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D)

217 GWAS identified one genome-wide significant hit (Affymetrix id 1:64178756_C_T; P=1.36 x 10(-11)).

218 ms (SNPs) selected from the most significant hits in the HD study.

219 ization of the benzene-sulfonamide in silico hit compound 3.

220 From a single hit (12) validated by biochemical and biophysical assays

221 gments in pools of eight identified a single hit that bound in a novel pocket in the protein.

222 ility, concavity, and whether it is a single-hit model.

223 Among the phospho-site hits were known LRRK2 sites as well as two phospho-sites

224 Seven associated SNPs hit directly on candidate genes; four SNPs were in high

225 tabolites are emerging as promising starting hit compounds to modulate human targets, hence triggerin

226 In winter 2013/14 a succession of storms hit the UK leading to record rainfall and flooding in ma

227 ated with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene fo

228 luciferins, and orthogonal enzyme-substrate "hits" were identified.

229 Potency optimization of the sulfonamide hit compounds was undertaken as informed by docking stud

230 Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by opti

231 This work demonstrates that hit-and-run epigenetic events can prevent senescence ent

232 trol continuum, measuring interventions that hit clinically related targets, and leveraging technolog

233 r the western North Pacific, especially that hits Korea and Japan.

234 nstantly encodes the visual information that hits the retina, leading to a stimulus-specific activati

235 The hit frequency was low overall, with median values of two

236 The hit validation stage of a fragment-based drug discovery

237 s at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requ

238 placement term can substantially improve the hit rates and ligand geometries from docking screens, al

239 ing design would have missed, increasing the hit frequency from the chemical library three-fold.

240 Optimization of the hit compound, identified in a NF-kappaB reporter gene as

241 positive hit compound and two analogs of the hit with high cytotoxic, pro-apoptotic and anti-mitotic

242 The hits were evaluated in biology triage assays to exclude

243 Among the hits that passed this screening cascade, a 6-dialkylamin

244 Up to 68% of the hits are chemotypes described for the first time as late

245 Herein we report optimization of the hits into potent small molecule inhibitors (IC50 < 300 n

246 One of the hits, MS0021570_1, was identified as a GPR171 antagonist

247 cal antipsychotic aripiprazole as one of the hits.

248 s on transcriptional regulation such as the "hit-and-run" model and transcription bursting that could

249 PAINS substructures were detected, and their hit rates were determined.

250 These hits provide insight into human vertebral segmentation d

251 Two of these hits (I942 and I178) were selected for their robust and

252 We report replication of these hits in published GWA studies of cognitive function, edu

253 Validation of one of these hits, confirmed NT5C (5',3'-Nucleotidase, Cytosolic) as

254 Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic

255 rbations in human cells and translated these hits into effective drug combinations.

256 mpound libraries identified more than thirty hits that increased MBNL1 expression greater than double

257 in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior.

258 The three "hits" had cumulative effects on ultrasonic vocalizations

259 Here we investigate whether a "three-hit" (genetic load x environmental factor x sex) theory

260 and structure-activity relationships through hit expansion guided by three-dimensional structures of

261 stability problem for PSCs and allow them to hit the market as a serious low-cost competitor to silic

262 ith the ubiquitin ligase Nedd4-1 being a top hit.

263 icro1) of the clathrin adaptor AP-1 as a top hit.

264 Further characterization of the top hit compound revealed its ability to induce a dose-depen

265 i-randomly mutated Oryza sativa FNR, the top hit enabled a 60 % increase in NADPH-driven H2 productio

266 ning data, we focused our studies on the top hit from our screen, the lipid kinase phosphatidylinosit

267 ); empirical PG x E=1.2 x 10(-8)) as the top hit.

268 Top hits (P < 5 x 10(-8)) were further evaluated in 291 CAD

269 Top hits were structurally unrelated BETi, including JQ1, I-

270 synthesis, out of 593 hits, 39 were left top hits.

271 The top hits based on the combined data-replication factor C3 (R

272 Third, the top hits with p<5.0x10(-6) from the first two stages were co

273 AS findings were made and focused on the top hits.

274 ormal development in mice, was among the top hits.

275 egative pathway components and validated top hits using multiple signaling and differentiation assays

276 Traditional hit-to-lead optimization assumes that upon elaboration o

277 ferred to as double-hit lymphomas (or triple-hit lymphomas if all 3 rearrangements are present).

278 e) out of seven tested candidates ( 40% true hit rate) as direct inhibitors of VCP/p97 and ERAD.

279 the view of LIP-driven autoimmunity as a two hit model; however, not all cofactors have equal ability

280 In this article, we describe two hit finding approaches leading to the discovery of new c

281 Two hits, ATA and NF023, obtained in both screens were confi

282 Further characterization of two hits revealed that the small molecule HDAC inhibitors, I

283 /obliterative arteriopathy induced via a two-hit pathophysiological mechanism without hypoxia provide

284 Here we establish a "two-hit" stress model in mice wherein stress at a specific p

285 Here we use a 'two-hit' immune-activation paradigm to determine whether per

286 Furthermore, in a 'two-hit' pneumonia model in mice, we have been able to demon

287 LI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and

288 These findings challenge the assumed two-hit model of Emu-Myc lymphoma and demonstrate a function

289 Our study identifies a potential "two-hit" mechanism in which tau acetylation disengages tau f

290 Testing the two-hit mouse model should both add new knowledge to the gro

291 , we say that a set of k-mers is a universal hitting set (UHS) if every possible L-long sequence must

292 pers to use an ordering based on a universal hitting set or, if not possible, a randomized ordering,

293 By using small universal hitting sets (a recently defined concept), we show how t

294 ll, the generated models can support various hit identification tasks, including virtual screening, c

295 le testing (Benjamini-Hochberg) and verified hits using bisulfite PCR pyrosequencing and qPCR.

296 Nearly 30% of monitored seabed was hit each year, and just 7% of shallows were not hit.

297 In 2015-2016, both regions were hit by another drought.

298 A third of health-care services were hit more than once.

299 activated the default mode network, whereas hits in the picture memory test preferentially engaged t

300 t but also illustrated a unique way in which hits from orthogonal screening approaches complemented e