ライフサイエンスコーパス: IMiD

1 IMiD-based MDM2 PROTAC 8, which potently reduces MDM2 pr

2 IMiD-induced decrease of C/EBPbeta protein led to impair

3 IMiDs also block the stimulatory effect of insulinlike g

4 IMiDs are used in therapeutic combinations at all stages

5 IMiDs diminished interleukin-2, interferongamma, and IL-

6 IMiDs display pronounced antiproliferative effect agains

7 IMiDs immunomodulatory drugs, including lenalidomide and

8 IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN

9 IMiDs, including lenalidamide and thalidomide, are also

10 ps: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared wi

11 opment stage of the model, we identified 176 IMiD response genes that were differentially expressed b

12 ever, IKZF1 is substantially lower in 3 of 5 IMiD-resistant MM cell lines.

13 re differentially expressed before and after IMiD exposure using pharmacogenomic GEP data from patien

14 ges of resistance to immunomodulatory agent (IMiD)-based therapy.

15 Immunomodulatory agents (IMiDs) are a cornerstone of treatment for patients with

16 Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune

17 kylators, steroids, immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), histone deacetylase

18 a binding target of immunomodulatory agents (IMiDs).

19 86.5% were double refractory to a PI and an IMiD.

20 These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulatio

21 ed 3 prior lines of therapy incorporating an IMiD and PI.

22 revious reports does so in the absence of an IMiD.

23 and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively.

24 The subgroup with an IMiD-14 score higher than the cutoff was deemed to be IM

25 5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM).

26 that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth arrest of MM

27 ase in AGO2 and SALL4 protein expression and IMiD treatment was able to rescue the siCRBN effect to i

28 Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilize

29 Thalidomide- and IMiD-induced SALL4 degradation can be abrogated by CRBN

30 e hypothesize that proteasome inhibitors and IMiDs are highly active because malignant plasma cells a

31 sphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action.

32 iling revealed that targets of both WDR5 and IMiDs:CRBN were significantly repressed by treatment of

33 core higher than the cutoff was deemed to be IMiD-resistant.

34 105 patients (75%), were administered before IMiD-based salvage therapy.

35 immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most

36 nd use of IMiD-based therapy, delays between IMiD refills, and select health outcomes during the firs

37 thin CRL4(CRBN) and enantioselectively binds IMiDs.

38 Emerging evidence suggests that both IMiDs and PIs can have cardiovascular (CV) sequelae, whi

39 e, inhibition of the eIF4E-C/EBPbeta axis by IMiD compounds was not observed in IMiD-resistant MM cel

40 chanism underlying the activation of CRBN by IMiDs is well described, the normal physiological regula

41 raders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioav

42 combined the 14 genes to create a continuous IMiD-14 score and an optimal cutoff.

43 Immunomodulatory derivatives (IMiDs), along with proteasome inhibitors, are key compon

44 (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As(2)O(3) act d

45 the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to exert its therapeuti

46 tegy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate recept

47 e expression of immunomodulatory imide drug (IMiD)-sensitive neosubstrates using proteomic and bioche

48 eblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM).

49 Thalidomide and its immunomodulatory drug (IMiD) analogs, lenalidomide, and pomalidomide, dose-depe

50 RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received 3

51 (ASCT) and long-term immunomodulatory drug (IMiD) maintenance.

52 Immunomodulatory drug (IMiD) resistance is a key clinical challenge in myeloma

53 The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomid

54 of which had received immunomodulatory drug (IMiD) therapy.

55 Lenalidomide is an immunomodulatory drug (IMiD) with activity in lymphoid malignancies occurring p

56 otent analog of Thal, immunomodulatory drug (IMiD), on T cells.

57 s remain effective in immunomodulatory drug (IMiD)-resistant MM cells.

58 had received both an immune modulatory drug (IMiD) and proteasome inhibitor: (35 [73%] of 48) were re

59 Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) a

60 inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory.

61 ed resistance to the immunomodulatory drugs (IMiD) lenalidomide in a cereblon-independent manner and

62 ed by classical immunomodulatory imid drugs (IMiDs).

63 generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family.

64 While immunomodulatory imide drugs (IMiDs) have been authorised for treatment of haematologi

65 Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomi

66 xemplified by immune-modulatory imide drugs (IMiDs).

67 CRBN ligands, immunomodulatory imide drugs (IMiDs).

68 Early immunomodulatory drugs (IMiDs(TM)) target Ikaros and Aiolos degradation.

69 of retreatment with immunomodulatory drugs (IMiDs) among patients with multiple myeloma who received

70 degraders, including immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs)

71 n of the widely used immunomodulatory drugs (IMiDs) and novel CRBN E3 ligase modulator drugs (CELMoDs

72 The introduction of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has greatly impro

73 pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, an

74 Immunomodulatory drugs (IMiDs) are a major class of drugs for treating multiple

75 Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myelo

76 lidomide and related immunomodulatory drugs (IMiDs) exert their antitumor effects remains unclear.

77 Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multipl

78 mechanisms by which immunomodulatory drugs (IMiDs) induce thrombocytopenia.

79 Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are Food and Drug A

80 The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effectiv

81 The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response

82 pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for mult

83 The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide have

84 inding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma

85 and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatmen

86 include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoD

87 asome inhibitors and immunomodulatory drugs (IMiDs), resulting in a significant improvement in overal

88 all molecules termed immunomodulatory drugs (IMiDs).

89 ntitumor activity of immunomodulatory drugs (IMiDs).

90 ed neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription

91 he use of novel oral immunomodulatory drugs (IMiDs; lenalidomide and thalidomide) among beneficiaries

92 stance to immunomodulatory inhibitory drugs (IMiDs).

93 For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcripti

94 000 (introduction of immunomodulatory drugs [IMiDs]), respectively.

95 its potent analogs (immunomodulatory drugs [IMiDs]).

96 l and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple

97 hese mutations were undetectable at earlier, IMiD-sensitive time points.

98 We establish ZFP91 as a bona fide IMiD-dependent CRL4(CRBN) substrate and further show tha

99 Median out-of-pocket cost for the first IMiD prescription was $3,178 for LIS nonrecipients and $

100 if, related to the IKZF1/3 ZnF, critical for IMiD-dependent CRBN binding.

101 eblon (CRBN) is an essential requirement for IMiD action, the complete molecular and biochemical mech

102 ummary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical

103 in the model could provide novel targets for IMiD resistance and therapeutic intervention.

104 A role for IMiDs, perhaps in combination with chemotherapy or andro

105 xpression of C/EBPbeta rescued MM cells from IMiD-induced inhibition of proliferation, indicating tha

106 ggest which patients would benefit most from IMiD-based therapies.

107 dentify patients most likely to benefit from IMiDs and suggest direct TrxR or Trx inhibitors for MM t

108 with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that b

109 ral new agents, such as the third-generation IMiD pomalidomide, the second-generation PIs carfilzomib

110 However, IMiDs are known to be inherently unstable, readily under

111 Taking advantage of the immunocompetent IMiD-sensitive Vk*MYChCRBN murine model of MM, we optimi

112 including epothilones and immunomodulators (IMiDs), as well as other novel agents within the new lan

113 inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherap

114 Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce t

115 Notably, USP15 is highly expressed in IMiD-resistant cells, and depletion of USP15 sensitizes

116 that coregulates cell survival with IKZF1 in IMiD-resistant TCLs.

117 a axis by IMiD compounds was not observed in IMiD-resistant MM cells.

118 thy plasma cells, but was more pronounced in IMiD-refractory MM.

119 s CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use o

120 s to show that treatment regimens, including IMiDs in multiple myeloma (MM), lead to aromatase degrad

121 tients acquire genetic alteration of the key IMiD effector cereblon (CRBN) by the time they are pomal

122 urs via its association with CRBN at a known IMiD binding pocket.

123 fty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neopl

124 3,038 beneficiaries, 41% received first-line IMiDs.

125 down (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear f

126 Here, we mapped the minimal IMiD-responsive IKZF3 degron and show that this peptidic

127 utic efficacy of microenvironment-modulating IMiDs.

128 the design of future clinical trials, moving IMiDs to the forefront of combinatorial cancer immunothe

129 Pomalidomide is a new IMiD with high in vitro potency.

130 rrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike t

131 estigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing pat

132 these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degradin

133 izable platform for the targeted delivery of IMiD-based molecular glues and PROTACs to FOLR1-expressi

134 As our knowledge of IMiD mechanism of action has advanced, the ability to st

135 This region may represent a novel marker of IMiD resistance with clinical utility.

136 nly in the last decade that the mechanism of IMiD action has been elucidated; through binding to the

137 CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prio

138 rt investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in mu

139 ined validation cohorts from four studies of IMiD combination regimens: the TT3a trial (thalidomide i

140 in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were unde

141 wever, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS.

142 yzed associations between the LIS and use of IMiD-based therapy, delays between IMiD refills, and sel

143 es both delineate the mechanism of action of IMiDs against MM cells in vitro and form the basis for c

144 myeloma; however, the mechanism of action of IMiDs is largely unknown.

145 CRBN is required for the action of IMiDs, but its protein expression levels do not correlat

146 ecent findings on the mechanism of action of IMiDs, its use as a new treatment modality for various h

147 ide teratogenicity and antitumor activity of IMiDs (now known as Cereblon E3 ligase modulators: CELMo

148 thalidomide, in the antimyeloma activity of IMiDs.

149 thway did not block the anti-PEL activity of IMiDs.

150 ects may refine the specific applications of IMiDs and improve the design of future clinical trials,

151 Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the

152 nockdown of MYC enhanced the cytotoxicity of IMiDs.

153 on the recent advances in the development of IMiDs.

154 in propagating the antiangiogenic effects of IMiDs in vitro.

155 The anti-PEL effects of IMiDs involved cereblon-dependent suppression of IRF4 an

156 Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of

157 d in mediating the antiangiogenic effects of IMiDs remains unclear.

158 s responsible for the pleiotropic effects of IMiDs, yet its function in angiogenesis and in mediating

159 may enhance immune response and efficacy of IMiDs in MM.

160 es investigated the pleiotropic functions of IMiDs, with a particular focus on immune modulation, the

161 rtance to clarify the antitumor mechanism of IMiDs.

162 er research into the molecular mechanisms of IMiDs and an increased understanding of their immunomodu

163 clinical data to highlight the relevance of IMiDs in combinatorial immunotherapy for both haematolog

164 compelling evidence for clinical testing of IMiDs alone and in combination with BRD4 inhibitors for

165 order to establish better clinical usage of IMiDs, it is of utmost importance to clarify the antitum

166 More and more indications for the use of IMiDs in hematologic malignancies have been identified.

167 tients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia

168 This review explores the existing work on IMiD resistance and proposes areas of future research th

169 ntiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still b

170 It exhibits strong selectivity over IMiD neo-substrates, favorable solubility, metabolic sta

171 linical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve p

172 s derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of haematologic malignan

173 ism of IMiD resistance in MM and may predict IMiD response prior to treatment.

174 anscript (exon 10 spliced), with progressive IMiD exposure, until almost one-third of patients had CB

175 ast to down-regulation of C/EBPbeta protein, IMiD compounds did not alter C/EBPbeta mRNA levels or pr

176 In those not receiving IMiD maintenance, CHIP is associated with decreased over

177 95% CI, 16% to 47%) probability of receiving IMiDs among beneficiaries age 75 to 84 years and a signi

178 First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-gener

179 erapy of multiple myeloma followed by repeat IMiD (thalidomide [34; 24%] or lenalidomide [106; 76%])

180 ieved less than a partial response to repeat IMiD.

181 Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in

182 ducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of gen

183 epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re

184 Although Thal/IMiDs, PS-341, and As(2)O(3) inhibit nuclear factor (NF)

185 e potential immunomodulatory effects of Thal/IMiDs in MM were examined.

186 It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act a

187 mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM c

188 cells by autologous PBMCs treated with Thal/IMiDs was also observed.

189 Immunomodulatory derivatives of thalidomide (IMiD compounds), such as pomalidomide and lenalidomide,

190 immunomodulatory derivative of thalidomide (IMiD) CC-5013 induces apoptosis or growth arrest even in

191 Immunomodulatory derivatives of thalidomide (IMiDs) have been used for the treatment of myelodysplast

192 immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented M

193 Here we show that IMiD compounds down-regulate CCAAT/enhancer-binding prot

194 Here, we report that IMiDs work primarily via inhibition of peroxidase-mediat

195 Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in common

196 We show that IMiDs down-regulate PU.1, a key transcription factor inv

197 It was shown that IMiDs impart gain-of-function properties to the CUL4-RBX

198 Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding t

199 The IMiD-14 model warrants evaluation in prospective studies

200 ity of CRBN to interact with CK1alpha at the IMiD binding pocket within the CRBN-CK1alpha complex.

201 free survival was 52% (95% CI 42-64) for the IMiD-14 high group versus 85% (78-92) for the IMiD-14 lo

202 MiD-14 high group versus 85% (78-92) for the IMiD-14 low group, with a hazard ratio (HR) of 2.51 (95%

203 ed to characterize second tumor risks in the IMiD era.

204 oint was to show the prognostic value of the IMiD-14 gene signature for progression-free survival.

205 INTERPRETATION: Our results suggest that the IMiD-14 model has prognostic value in patients with mult

206 comes when delivered in combination with the IMiD derivatives lenalidomide or pomalidomide.

207 Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversel

208 the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tum

209 poptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion

210 ensor, the auxin perception complex, and the IMiDs-bound CRL4(CRBN) E3, which can bind and ubiquitina

211 mide-like molecules (collectively called the IMiDs) bind to the ubiquitously expressed cereblon ubiqu

212 osts for expensive anticancer drugs like the IMiDs may improve access to oral therapy for patients wi

213 n the present study, we demonstrate that the IMiDs trigger activation of caspase-8, enhance MM cell s

214 1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner.

215 trate degradation and cell death even though IMiDs were not active.

216 n and its pathway are known to contribute to IMiD resistance, they account for only 20% to 30% of cas

217 alyzing whether any mutations deleterious to IMiD action could be overcome using the novel cereblon E

218 driver of poor prognosis which may be due to IMiD resistance.

219 an time from diagnosis to repeat exposure to IMiD was 28 months.

220 nsitivity of human multiple myeloma cells to IMiDs.

221 show that 2 factors determine resistance to IMiDs among TCLs.

222 ultiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease.

223 o not correlate with intrinsic resistance to IMiDs in MM cells, suggesting other factors involved in

224 yeloma (MM); however, acquired resistance to IMiDs remains a significant clinical challenge.

225 factors involved in regulating resistance to IMiDs.

226 ll patients eventually develop resistance to IMiDs.

227 le myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degra

228 k patients who exhibit poor response towards IMiD-based regimens.

229 hat we believe a critical mechanism by which IMiDs drugs function as therapeutic immunomodulatory age

230 cereblon-independent pathways, through which IMiDs exert their antiangiogenic effects.

231 netic disruption by mutation associated with IMiD resistance.

232 d acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure.

233 ignificantly shorter in the 83 patients with IMiD-14 high scores than in the 92 patients with IMiD-14

234 -14 high scores than in the 92 patients with IMiD-14 low scores; 3 year progression-free survival was

235 oma who were treated in clinical trials with IMiD-containing regimens.

236 evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.

237 e-binding pocket but is not competitive with IMiDs.

238 t heterologous proteins for destruction with IMiDs in a time- and dose-dependent manner in cultured c

239 ion causes resistance and poor outcomes with IMiDs.

240 himeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo.

241 Patients treated with IMiDs had significantly fewer emergency department visit

242 s with multiple myeloma who are treated with IMiDs.

243 n effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression.

244 ients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistanc

245 ith IMiD exposure, but none in cases without IMiD exposure.

246 with patients receiving bortezomib (without IMiDs), but 1-year overall survival and cumulative Medic