ライフサイエンスコーパス: HIT

1 ants and thus were termed as "repositionable hits".

2 combinations of multiple genetic mutations (hits).

3 ghput insertion tracking by deep sequencing (HITS).

4 l product jawsamycin (FR-900848) as a potent hit.

5 on may provide a new therapeutic approach to HIT.

6 ough optimization of a 6-azaindole screening hit.

7 uate thrombus formation in a murine model of HIT.

8 atives were synthesized based on a screening hit.

9 culosis identified 1, a thioalkylbenzoxazole hit.

10 teomic analysis identified Rab7-S72 as a top hit.

11 es and propensities to acquire an additional hit.

12 nitial management of patients with suspected HIT.

13 rug screens in C. elegans which uncovered 74 hits.

14 or identifying combinations of more than two hits.

15 erized detailed mechanistic functions of two hits.

16 support a facile method for affinity-ranking hits.

17 ncers are estimated to require three or more hits.

18 re enriched for coronary artery disease GWAS hits.

19 le counter screen to remove undesirable FRET Hits.

20 nd candidate genes occurring within the GWAS hits.

21 e series was the moderate potency of the HTS hits.

22 A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was s

23 Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led

24 een was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for

25 ent the chemical optimization of our initial hits, 2-oxo-4-phenyl-N-(4-phenylbutyl)oxazole-3-carboxam

26 NF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognos

27 ided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) fr

28 The HIT-2000-BIS4 trial aimed to avoid highly detrimental cr

29 l high-throughput screening campaign emerged hit 3 among others.

30 tructure-guided optimization of the pyridone hit 3 using this biochemical assay in combination with c

31 Compared with the initial hit, 36 showed improved potency in a guanosine 5'-O-[gam

32 ant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), m

33 al optimization of high-throughput screening hit 8 to a potent, metabolically stable, and orally bioa

34 The impact hit a carbonate platform and released sulfate aerosols a

35 niches become increasingly filled, diversity hits a plateau (as predicted by EC).

36 agnosis of heparin-induced thrombocytopenia (HIT), a difficult-to-diagnose immune-related complicatio

37 lopment of heparin-induced thrombocytopenia (HIT), a potentially fatal immune disorder affecting 1-5%

38 From this set of hits, a cluster of diaminopurine-derived compounds was i

39 gely divergent results, with few overlapping hits across different studies.

40 We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds

41 r matrix based CPU implementation, for the 3-hit algorithm, allowing us to identify 3-hit combination

42 tion strategies, and molecular properties of hits and leads are presented in the hope of informing be

43 reward structure (ratio of points for target hits and misses) for different exploitation horizons (i.

44 through automated screening techniques; many hits and some new mechanisms involved in axonal regenera

45 hysically attacked the snake (with bites and hits), and pulled the victim to safety.

46 compounds were identified as validated lead-hits, and four were prioritized for further study (endos

47 r subpopulations can promote metastases via "hit-and-run" commensal interactions.

48 Relevant double-hit animal models have provided clues to whether and how

49 hat peri-thrombus endothelium is targeted by HIT antibodies, but the binding site(s) has not been ide

50 Disruption of PF4-VWF-HIT antibody complexes by drugs that prevent or block VW

51 Platelet adhesion to the PF4-VWF-HIT antibody complexes is inhibited by antibodies that b

52 In this study, we investigated a "double-hit" approach on primary human endothelial cells primed

53 gets identified as proxies of direct genetic hits are enriched for successful drug targets, as measur

54 n adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitiz

55 elucidating molecular mechanisms underlying HIT, as well as other physiological processes driven by

56 avored lipophilic hits, the average clogP of hits at a given target did not correlate with its hit ra

57 at span the entire active site, as well as 3 hits at the dimer interface.

58 orithm for heparin-induced thrombocytopenia (HIT) based on the 4Ts score and 2 rapid immunoassays (IA

59 were binned into 1,566 different best BLAST hits (BBHs) and counted for each mouse sample.

60 nvolved in heparin-induced thrombocytopenia (HIT), beta-2-glycoprotein-1 implicated in antiphospholip

61 hanges), and 13 fall within loci recurrently hit by copy number variants.

62 e diagnostic rubric for the determination of HIT by leveraging machine-learning-based classification

63 ificance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-

64 ally and in many of the U.S. regions hardest hit by the pandemic.

65 polyketides Aureothin/Neoaureothin as potent hits by anti-HIV screening of an extensive natural compo

66 s spectrometry followed by validation of the hits by biochemical and functional analyses.

67 Hits can be profiled to determine potency and the site o

68 sequencing crosslinking immunoprecipitation (HITS-CLIP) and biochemical analyses revealed direct bind

69 of carcinogenic genes with mutations (multi-hit combinations), which could suggest a likely cause fo

70 e 3-hit algorithm, allowing us to identify 3-hit combinations.

71 oughput virtual screening led us to identify hit compound 5, endowed with promising antienzymatic act

72 ucture of H1/PR8 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets

73 In mice, the hit compound increased body temperature, UCP1 protein le

74 We discovered the hit compound NR-160 by investigating the inhibition of r

75 this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a l

76 geminal dimethylindoline core of the initial hit compound to a spiroindoline system significantly imp

77 A potent hit compound was discovered containing a (R)-N-(piperidi

78 SAR studies on the initial hit, compound 4 (IC(50) = 257 nM), resulted in several h

79 ing wet-laboratory experiments, poor initial hit compounds and the high attrition rates in the (pre-)

80 rformed on dozens of candidate molecules and hit compounds can be conveniently resynthesized on DNA.

81 Hit compounds in this series display sub-micromolar in v

82 Counterscreening of the hit compounds provided an assessment of their selectivit

83 Target analysis of hit compounds revealed androgen signaling as a key modul

84 In addition, our hit compounds show good activity against the liver stage

85 Hit compounds showed moderate asexual blood stage activi

86 compounds was conducted, resulting in three hit compounds with the desired selectivity profile.

87 tion assay, we obtained only a low number of hit compounds.

88 o clear boundary between normal and frequent hitting compounds.

89 whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting.

90 pecific protein domains and to normalize the hit-counts based on the domain length.

91 ceutical companies due to their potential to hit currently "undruggable" targets.

92 Significant, and independently validated, hits demonstrated the importance of multiple protein fam

93 (TMPA), and three high-throughput screening hit derivatives.

94 A benzamide pyridine hit derived from a focused screen was successfully devel

95 confirmed by HIPA: 10 patients with probable HIT despite negative HIPA and 2 possible false-positive

96 this strategy which has great potential for hit discovery and hit or lead optimization.

97 a valuable technology for democratizing the hit discovery process.

98 e interaction, and it was confirmed that one hit disrupted VPS34 Complex I formation and inhibited au

99 Among the hits, domperidone emerged as an effective corrector that

100 nologies result in an extensive attrition of hits during validation experiments.

101 y" (i.e., stability) counteracted the double-hit effect on neutrophil TEM.

102 maker accumulates evidence until the process hits either an upper or lower stopping boundary and then

103 ad of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogr

104 pite being a critically important element in HIT etiology, relatively little is known about the speci

105 This was followed by hit expansion and analogue synthesis to further improve

106 work demonstrates a powerful new approach to hit-finding.

107 Those who reported >=1 hit followed by loss of consciousness, compared to those

108 rting from an in-house proprietary screening hit followed by structure-based rational design, we have

109 Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments wer

110 tial to find clinically useful high-affinity hits for the rapid discovery of drugs for targets (e.g.,

111 Hit frequency was largely independent of library size an

112 ver, treatment of parasites with a screening hit from the malaria box compound collection, MMV007839,

113 We further characterized a top hit from the screen, progenitor renewal associated non-c

114 The top hit from these screens was GSG2 (also known as Haspin),

115 EC(50)/IC(50) kinetic model fits, as well as hits from high-throughput screening assays.

116 The hits from HTS were further screened for their AChE inhib

117 slating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse cli

118 se assays to experimentally validate several hits from our primary data, as well as variants for whic

119 , or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensi

120 oal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridine

121 One of the top hits from the screen was RAP80, a protein that recruits

122 To validate these hits from the screen, we developed patient-derived xenog

123 Hits from the selection were rigorously analyzed to dete

124 Positive hits from this initial screen were then further narrowed

125 The hits from this unbiased screen and the mechanistic valid

126 ons in tumor and normal samples in the multi-hit gene combinations can suggest potential driver mutat

127 st competition assay and its application for hit generation of dual TLR7/8 antagonists are reported.

128 In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-

129 rt and a validation cohort (n = 71) from the HIT group and Russia.

130 brary to identify a promising small molecule hit (GY1-22) against the interacting pocket in the DNAJA

131 tal surfaces (HITES), interrupting the virus-HITES-hands nexus.

132 inal chemistry optimization, the most potent hit has IC(50) 280 nM, corresponding to K (i) of 173 nM.

133 CI: 0.0, 3.3) and reporting a partner would hit her if she asked him to wear a condom (indirect effe

134 The dual hit hypothesis about the pathogenesis of Parkinson disea

135 Surprisingly, in contrast to Knudsen's two hit hypothesis, the p.S745L somatic mutation was always

136 Here, we present a hit identification approach using AtomNet, the world's f

137 To automate hit identification, we developed a machine-learning mode

138 ient sampling of the vast chemical space for hit identification.

139 The hits identified in this analysis included specific genes

140 derived algorithm (n = 687), HemosIL-AcuStar-HIT-IgG was used as unique testing in 566 (82.4%) of 687

141 ositive HIPA were >3.0 U/mL (HemosIL-AcuStar-HIT-IgG) and titer >=16 (ID-H/PF4-PaGIA); cutoffs with 1

142 nalyzed by Zymutest-HIA-IgG, HemosIL-AcuStar-HIT-IgG, and ID-H/PF4-PaGIA in retrospective (n = 221) a

143 st a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmenta

144 iple myeloma cells in this way take a double hit: immunoproteasome inhibition and doxorubicin-induced

145 vasion screen, which identified two separate hits, IMPAD1 and KDELR2, as robust, independent drivers

146 ing of the library beads allowed recovery of hits improved in Kd over wild-type ZIgE by up to 3.5-fol

147 -based virtual screening, the quality of the hits improves with the number of compounds screened(2).

148 antibodies is accurate for ruling in or out HIT in >=95% of cases within 60 minutes.

149 -based SERS analytical tool for diagnosis of HIT in the clinical laboratory, without perturbing the e

150 er microvascular injury in a murine model of HIT in which human FcgammaRIIa was expressed as a transg

151 4 additional families having single allelic hits in MFRP or PRSS56 (7.5%).

152 o hits in ~16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, underst

153 arallel evolution, including distinct second hits in SMARCA4, a putative predisposition gene for neur

154 studies of depression, from identifying zero hits in ~16 000 individuals in 2013 to 223 hits in more

155 usative role for plasmin (ogen) as a "second hit" in kidney disease progression has yet to have been

156 FRA, the concentration ratio for the top 30 "hits" in each comparison was obtained and then t-tested

157 These hits included expected PI3K interactors, such as the pla

158 Interestingly, the double-hit-induced TEM increase was not due to decreased endoth

159 aminating high-touch environmental surfaces (HITES), interrupting the virus-HITES-hands nexus.

160 were assigned and used to categorize the NMR hits into different classes.

161 A second, cooperating genetic hit is often required to push these hyperplastic cells t

162 MALDI-HiTES is a broadly applicable tool for the discovery of

163 Among ~550 identified screen hits is MLX, a basic helix-loop-helix leucine-zipper tra

164 Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by complexes b

165 suspected heparin-induced thrombocytopenia (HIT) is critical for guiding initial patient management.

166 ent regulatory genes that serve as a "second hit," leading to uncontrolled complement activation and

167 by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecule

168 The HIT-like monoclonal antibody KKO and HIT patient antibod

169 CNVs hitting loss-of-function intolerant genes were associate

170 er BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed

171 ithm scales exponentially with the number of hits, making it impractical for identifying combinations

172 mparing the samples, the counts of localized hits matching the domains of interest were normalized to

173 etitive displacement assay to identify novel hit matter.

174 atterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivor

175 arated in time and space, supporting a multi-hit model in which emergence of autoreactive T cells is

176 We previously proposed a two-hit model in which the mouse gastrointestinal Chlamydia

177 e presence of amyloid, consistent with a two-hit model of AD on cognition.

178 D-like aberrations in mice using a novel two-hit model.

179 Starting from an initial hit molecule, we report its divergent optimization towar

180 We explore the numerous hit molecules beginning to emerge from high-content/high

181 ic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting.

182 d one of the high-throughput screening (HTS) hits, N(2)-(thiophen-3-yl)-N(6)-(2,2,2-trifluoroethyl)-9

183 Intersection of screen hits obtained from two cell lines and orthogonal approac

184 rting from a high-throughput screening (HTS) hit of our corporate compound library, multiple paramete

185 The top hit of the screen is the cytosolic Malic Enzyme (ME1), t

186 use gene knockouts identified 140 monogenic 'hits', of which most had no previous immunologic associa

187 al screen advanced 38 compounds as potential hits, of which, four compounds enhanced endothelial barr

188 These combined hits offer unprecedented structural and reactivity infor

189 erging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent f

190 Small structure modifications to hit or lead compounds can have meaningful impacts on pha

191 duration of design cycles needed to optimize hit or lead compounds into high-quality chemical probes

192 n aromatic or heteroaromatic ring-containing hit or lead compounds is one approach toward minimizing

193 ch has great potential for hit discovery and hit or lead optimization.

194 f MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lympho

195 16 within the Class II HLA region as the top hit (P = 2 x 10(-14)); this was in linkage disequilibriu

196 The HIT-like monoclonal antibody KKO and HIT patient antibodies recognize PF4-VWF complexes, prom

197 ion and poor outcomes were specific to multi-hit patients only.

198 nd estimated viral loads based on the single-hit Poisson model were compared, and a hybrid Poisson di

199 The AMI-MS assay identified 86% of hits previously identified, with a pIC(50) >= 5.0, in a

200 ng a using an algorithm that we designed for hit prioritization that we call Hit to Lead Prioritizati

201 5-fold, while a consensus mutant of the best hits provided a 10-fold improvement.

202 we adapted an inhibitory avoidance-based "2-hit" rat model of posttraumatic stress disorder (PTSD) a

203 llation proximity assay (SPA) HTS at a lower hit rate and with a significantly reduced cost per well

204 ive test, specificity improved to 93.4%, but hit rate decreased to 21.0%.

205 At the same specificity, the hit rate for trend-based analysis was significantly grea

206 peutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2

207 The exceptionally low hit rate observed here suggests that PrP is a difficult

208 We found validated ligands with a high hit rate of 29% out of those tested, none of them showin

209 and obtained 6 X-ray co-structures, giving a hit rate of 40%.

210 eened on hMC4R, this bank gave an incredible hit rate of 8%.

211 The approach is effective, with an overall hit rate of ~30% at 30 muM and discovery of potent compo

212 d analysis still had a significantly greater hit rate than the rule of 5 (47.4% vs. 21.0%, respective

213 of 5 to allow meaningful comparison of the "hit rate," or the proportion of glaucoma eyes categorize

214 at a given target did not correlate with its hit rate.

215 ness criteria (mainly MW, clogP) reduces the hit rates of attractive chemical starting points in subs

216 Hit rates of these targets as well as physicochemical pr

217 Hit rates were reduced, and reaction times increased for

218 modified approaches of reciprocal best BLAST hits (RBH) and UCLUST.

219 e spread of SARS-CoV-2, particularly in hard-hit regions.

220 e for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-ph

221 nk, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score pr

222 Noncovalent fragment hits revealed binding hotspots, while the covalent inhib

223 leration (adjusted p = 0.0049), time between hits rotational acceleration (adjusted p value 0.0101),

224 encoding the phage receptor(s) were the top hit(s) in the analyses of the successful screens.

225 Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their ex

226 sulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities aga

227 he optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a he

228 Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 12

229 ntify that published synthetic lethal screen hits significantly overlap at the pathway rather than ge

230 onmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotre

231 TP53 multi-hit state predicted risk of death and leukemic transform

232 by immunohistochemistry and double or triple hit status was determined by cytogenetics.

233 the high cost of conference attendance might hit students and early-career researchers the hardest.

234 in, we describe the synthesis of our initial hit TCMDC-135051 (1) and efforts to establish a structur

235 found the anticancer drug sorafenib as major hit that effectively kills MRSA strains.

236 ghput screen and discovered a small molecule hit that is highly selective for ERAP1.

237 initial screen of 2560 molecules yielded 19 hits that effectively disrupted the interaction, and it

238 an glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinical

239 We identified nine Hits that reduced FRET between Lifeact and ABD.

240 Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits

241 We identified 27 hits that were ranked using a using an algorithm that we

242 ng, and further characterization of positive hits (that is, IC(50) and K(i) ), as well as inhibition-

243 These results suggest that East Asians hit the bamboo ceiling because their low assertiveness i

244 ics of the common cold and influenza disease hit the human population like clockwork in the winter se

245 Pupil diameter determines how much light hits the retina and, thus, how much information is avail

246 ng account.SIGNIFICANCE STATEMENT When light hits the retina, the pupil reflexively constricts.

247 caused by 88 tropical storms and hurricanes hitting the United States between 1996 and 2016 and show

248 COVID-19 has been sweeping the globe, hitting the United States particularly hard with a state

249 Although most targets favored lipophilic hits, the average clogP of hits at a given target did no

250 nalyzed in more depth, giving 75 examples of hit to lead development.

251 Hit to lead optimization using an iterative structure-ba

252 designed for hit prioritization that we call Hit to Lead Prioritization Score (H2LPS).

253 intestinal Chlamydia might induce the second hit to promote genital tract pathology, and we are now p

254 l dominant tumor syndrome resulting from two hits to the same allele of PLCD1 tumor suppressor gene.

255 ble functional group can be found in various hit-to-lead and lead optimization studies in early stage

256 We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrim

257 e compound screening campaign and a rigorous hit-to-lead flowchart combining biochemical and biophysi

258 The hit-to-lead optimization led to the discovery of a novel

259 Subsequent hit-to-lead optimization, using cocrystal structures of

260 ting point for a structure-based drug design hit-to-lead program.

261 by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phox(SH

262 chromosome 4D identified two candidate gene hits, TraesCS4D02G352200 (TaNox8; an NADPH oxidase) and

263 We designed a double-hit treatment that allows iNKT cells to escape anergy an

264 Evaluation of the top scoring hit, Trichostatin A (TSA), demonstrated utrophin upregul

265 scribed, and the development of the fragment hits using a fragment growing strategy was employed, whi

266 context of DNA-encoded libraries, for which hit validation procedures need to be performed on dozens

267 A high-throughput screening hit was modified at three different substituents to opti

268 The top association hit was Ncc69 (human NKCC1/2), a conserved ion transport

269 Unexpectedly, one top hit was Traf3, a negative regulator of NF-kappaB signali

270 Among the top hits was MAX, the obligate heterodimerization partner fo

271 Unexpectedly, one of the top 'hits' was a GSK3 inhibitor, an agonist of Wnt signaling.

272 From 366 screen hits we further validated the antiplasmid activity of ka

273 Starting from a non-selective screening hit, we have achieved the goal of discovering molecules

274 Using the FRET Hits, we show that our counter screen is sensitive to un

275 To identify combinations of greater than two hits, we used a compressed binary matrix representation,

276 Here, semisynthetic analogues of hit were designed, synthetized, and tested against colis

277 he primary screen revealed 44 non-antifungal hits were able to act synergistically with fluconazole a

278 Positive hits were assessed for AR subtype selectivity through cA

279 Furthermore, hits were collectively enriched in genes for which human

280 The strongest hits were components of the ESCRT complexes.

281 well as physicochemical properties for those hits were evaluated.

282 Four of those Hits were found to reduce Lifeact cosedimentation with a

283 Hits were further characterized and validated using a se

284 Nevertheless, several hits were identified as Lessonia exclusive or more remar

285 ossible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who

286 otential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correla

287 is linked to UBQLN2 function, the strongest hits were the ubiquitin ligase TRIM32 and two retroeleme

288 Hits were triaged based on potency and physicochemical p

289 Several hits were validated using a DNAJA1 inhibitor (116-9e) in

290 The top 10 hits were validated using an orthogonal assay for endoge

291 approaches to elaborate the initial fragment hits, which usually bind with low affinity to their targ

292 y for the target RNA relative to the initial hits, while also having significantly improved drug-like

293 ed a chemically well-behaved, first-in-class hit with nanomolar anti-RABV potency that blocks RABV G

294 a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties.

295 ructure-based approach, we merged a fragment hit with the previously reported sulfonamide series.

296 A majority of targets yielded hits with higher clogP, molecular weight, and more basic

297 against MRSA (USA300) revealed several lead hits with improved activity over methicillin.

298 ation of high-throughput elicitor screening (HiTES) with matrix-assisted laser desorption/ionization

299 their ability to replace OCH as the initial hit, with their lipid chain length being a determinant o

300 Since the COVID-19 pandemic first hit Wuhan, China, in December 2019, scientists have been