Amino-substituted thalidomide analogs: Potent inhibitors of TNF-α production

Muller, George W.; Chen, Roger; Huang, Shaei‐Yun; Corral, Laura G.; Wong, Lu Min; Patterson, Rebecca T.; Chen, Yuxi; Kaplan, Gilla; Stirling, David I.

doi:10.1016/s0960-894x(99)00250-4

Cited by 326 publications

(176 citation statements)

References 15 publications

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“…6 In contrast, the IMiDs are 50 000 times more potent than thalidomide in inhibiting TNF-␣ production from LPSstimulated peripheral blood mononuclear cells in vitro. 15,16 Although these analogs are also more potent inducers of T cell proliferation and secretion of IFN-␥ and IL-2, 9 we were unable to show CTL activity. 6 However, these drugs augmented natural killer cell cytotoxicity against autologous MM cells, 6 and inhibit IL-1␤ and IL-6 secretion from PBMCs.…”

Section: Figurementioning

confidence: 74%

“…6 However, these drugs augmented natural killer cell cytotoxicity against autologous MM cells, 6 and inhibit IL-1␤ and IL-6 secretion from PBMCs. 9 We first demonstrated a direct effect of the IMiDs against human MM cell lines and patient cells in vitro, including drug-resistant cell lines: IMiD1 and IMiD3 achieved 50% inhibition of DNA synthesis at concentration (0.01-0.1 M), corresponding to serum levels that are readily achievable. 10 These drugs induce either growth arrest or apoptosis, associated with activation of RAFTK, in both MM cell lines and patient cells.…”

Section: Figurementioning

confidence: 99%

“…Besides alkylating agents, corticosteroids and anthracyclines, thalidomide therefore represents a novel class of agents for the treatment of MM. [6][7][8] We have previously shown that the potent immunomodulatory thalidomide analogs (IMiDs) 9 induce a dose-dependent inhibition of proliferation, either apoptosis or growth arrest, even in MM cell lines and MM patient cells resistant to conventional chemotherapy. 10 Moreover, thalidomide and the IMiDs enhance the anti-MM activity of dexamethasone (Dex); and conversely, are inhibited by interleukin (IL)-6.…”

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo

et al. 2003

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We have previously shown that thalidomide and its potent immunomodulatory derivatives (IMiDs) inhibit the in vitro growth of multiple myeloma (MM) cell lines and patient MM cells that are resistant to conventional therapy. In this study, we further characterize the effect of these drugs on growth of B cell malignancies and angiogenesis. We established a beigenude-xid (BNX) mouse model to allow for simultaneous in vivo measurement of both anti-tumor and anti-angiogenic effects of thalidomide and its analogs. Daily treatment (50 mg/kg/d) with thalidomide or IMiDs was nontoxic. The IMiDs were significantly more potent than thalidomide in vivo in suppressing tumor growth, evidenced by decreased tumor volume and prolonged survival, as well as mediating anti-angiogenic effects, as determined by decreased microvessel density. Our results therefore show that the IMiDs have more potent direct antitumor and anti-angiogenic effects than thalidomide in vivo, providing the framework for clinical protocols evaluating these agents in MM and other B cell neoplasms.

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Section: Figurementioning

confidence: 74%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo

et al. 2003

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“…In actuality, each enantiomer may have unique pharmacological and safety profiles. Although there is limited data available and the enantiomers interconvert during the time course of the studies, a few groups have shown that the teratogenicity, in vitro antiinflammatory activity, and in vivo efficacy of protonated thalidomide analogs are caused, in large part, by the (S)-enantiomer (22,(36)(37)(38). (S)-pomalidomide was originally advanced into clinical trials as ENMD 0995 (39) but soon abandoned because of the rapid racemization of the exchangeable chiral center (28,29).…”

mentioning

confidence: 99%

“…Attempts to stabilize the (S)-enantiomer of thalidomide analogs have included replacement of the exchangeable hydrogen with methyl (20,37,41,42) or fluorine groups (43,44). If and when the stable enantiomer of these analogs was studied, none were superior to the racemic, protonated thalidomide analog.…”

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confidence: 99%

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Jacques¹,

Czarnik²,

Judge³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using “deuterium-enabled chiral switching” (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (−)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.

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