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CRBN), a Primary Direct Target of Thalidomide, Using Ferrite Glycidyl Methacrylate (FG) Beads

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CRBN), a Primary Direct Target of Thalidomide, Using Ferrite Glycidyl Methacrylate (FG) Beads No. 6] Proc. Jpn. Acad., Ser. B 96 (2020) 189 Review Molecular mechanisms of thalidomide and its derivatives † By Takumi ITO*1 and Hiroshi HANDA*1, (Edited by Shigekazu NAGATA, M.J.A.) Abstract: Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma, and derivatives such as lenalidomide and pomalidomide have been developed for treating blood cancers. Although the molecular mechanisms of thalidomide and its derivatives remained poorly understood until recently, we identified cereblon (CRBN), a primary direct target of thalidomide, using ferrite glycidyl methacrylate (FG) beads. CRBN is a ligand-dependent substrate receptor of the E3 ubiquitin ligase complex cullin-RING ligase 4 (CRL4CRBN). When a ligand such as thalidomide binds to CRBN, it recognizes various ‘neosubstrates’ depending on the shape of the ligand. CRL4CRBN binds many neosubstrates in the presence of various ligands. CRBN has been utilized in a novel protein knockdown technology named proteolysis targeting chimeras (PROTACs). Heterobifunctional molecules such as dBET1 are being developed to specifically degrade proteins of interest. Herein, we review recent advances in CRBN research. Keywords: thalidomide, lenalidomide, immunomodulatory imide drugs (IMiDs), cereblon, ubiquitin, proteolysis targeting chimeras (PROTACs) icity was detected when tested on rodents, and Introduction thalidomide was sold to more than 40 countries. In 1954, thalidomide (Fig. 1A) was developed as However, in the early 1960s, McBride and Lenz a sedative hypnotic drug by the German pharma- independently reported that thalidomide is highly ceutical company Grunenthal. No remarkable tox- teratogenic. When pregnant women take thalido- mide, newborn infants suffer severe developmental *1 Department of Chemical Biology, Tokyo Medical defects such as phocomelia and small ear. Although University, Tokyo, Japan. † this drug was withdrawn from the market, research- Correspondence should be addressed: H. Handa, Depart- ment of Chemical Biology, Tokyo Medical University, 6-1-1 ers continued studying its mechanism of action and – Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan (e-mail: hhanda@ activity.1) 3) tokyo-med.ac.jp). In 1965, an Israeli physician found that thalido- Abbreviations: AML: acute myeloid leukemia; BP: O- ff propeller; BRD4: bromodomain-containing protein 4; Cas9: mide is e ective for treating erythema nodosum CRISPR-associated protein 9; CDK9: cyclin-dependent kinase 9; leprosum, a specific type of leprosy resulting in CELMoD: Cereblon E3 ligase modulator; CK1,: casein kinase 1 painful skin lesions.4) During the 1980s and early alpha; CRBN: cereblon; CRISPR: clustered regularly interspaced 1990s, thalidomide was found to be an effective short palindromic repeats; CRL4: cullin-RING ligase-4; Cul4A: Cullin-4A; DDB1: damage-specific DNA-binding protein 1; treatment for certain autoimmune diseases, such as DLBCL: diffuse large B-cell lymphoma; DSIF: DRB-sensitivity rheumatoid arthritis and chronic graft versus host inducing factor; E2: ubiquitin conjugating enzyme; E3: ubiquitin disease,5)–7) and thalidomide decreases tumor ne- ligase; eRF3a: eukaryotic release factor 1a; FDA: Food and Drug , 8),9) fi crosis factor- production. In 1994, thalidomide Administration; FG: ferrite glycidyl methacrylate; FGF8: bro- 10) blast growth factor 8; GSPT1: G1 to S phase transition 1; IMiDs: was shown to inhibit angiogenesis, and in 1999, immunomodulatory imide drugs; KRAS: Kirsten rat sarcoma viral thalidomide was demonstrated to be effective for oncogene homolog; MEIS2: myeloid ecotropic integration site 2; the treatment of multiple myeloma.11) The use of PROTACs: proteolysis targeting chimeras; RING: really interest- thalidomide for treating erythema nodosum leprosum ing new gene; Roc1: Regulator of cullins-1; SALL4: spalt-like transcription factor 4; SG: styrene glycidyl methacrylate; SLE: and multiple myeloma was approved by the Food systemic lupus erythematosus; TBD: thalidomide-binding domain. and Drug Administration (FDA) in the U.S. in 1998 doi: 10.2183/pjab.96.016 ©2020 The Japan Academy 190 T. ITO and H. HANDA [Vol. 96, (A) (B) (C) (D) Thalidomide Lenalidomide Pomalidomide CC-885 phthalimide glutarimide isoindolinone (H) (E) (F) (G) CC-122 (avadomide) CC-220 (iberdomide) dBET1 Uridine H N O O HN O N O O N NO N O N O N N NH NH N O N O O O O NH S O NH2 O Cl JQ1 (binding to BRD4) Fig. 1. Structure of CRBN-binding drugs. (A) Thalidomide. (B) Lenalidomide. (C) Pomalidomide. (D) CC-885. (E) CC-122. (F) CC- 220. (G) dBET1, composed of JQ1 (a BRD4 inhibitor) and thalidomide. (H) Uridine. and 2006, respectively. In Japan, the use of thalido- now considered a primary direct target for both the mide for the treatment of multiple myeloma was anti-cancer activity and teratogenicity of thalido- approved in 2008. Because thalidomide is associated mide.26),27) with serious teratogenicity, its use is strictly con- CRBN forms a cullin-really interesting new gene trolled by the System for Thalidomide Education (RING) ligase-4 (CRL4) ubiquitin ligase (E3) com- and Prescribing Safety (STEPS) program in the U.S. plex with damage-specific DNA-binding protein 1 and the Thalidomide Education and Risk Manage- (DDB1), Cullin 4 (Cul4), and Regulator of cullins-1 ment System (TERMS) in Japan.12),13) Thalidomide (Roc1).25),28),29) When thalidomide or its derivatives represents one of the most successful cases of drug bind to CRBN, CRBN can recognize drug-dependent repositioning. ‘neosubstrates’ for subsequent ubiquitination and Recently, several thalidomide derivatives have protein degradation. Substrate selectivity is depend- been developed as immunomodulatory imide drugs ent on the structure of CRBN-binding com- (IMiDs).14),15) Among these, lenalidomide and poma- pounds,26),30) and novel medicines that target CRBN lidomide have potent anti-cancer activity (Fig. 1B are being eagerly sought. In particular, proteolysis- and 1C), both drugs exert clinically beneficial effects targeting chimeras (PROTACs) have been developed against multiple myeloma, and they have already using CRBN, and this technology is attracting the been approved by the U.S. and Japan. Lenalidomide attention of researchers and the pharmaceutical also possesses therapeutic activity for the treatment industry.31),32) of myelodysplastic syndrome (5q-), mantle cell In this review, we summarize the molecular lymphoma, and follicular lymphoma.16)–22) mechanisms of thalidomide and its derivatives. In The effects of thalidomide are pleiotropic, hence addition, we introduce various applications of thali- there are believed to be numerous molecular targets domide-like compounds, with particular emphasis on of this drug. The direct target of thalidomide was CRBN approaches. not known until recently due to technical limitations. However, our group developed new affinity matrices Development of drug target deconvolution (styrene glycidyl methacrylate [SG] and ferrite glyci- Identifying the direct target proteins of small dyl methacrylate [FG] beads) for isolating drug- chemical ligands such as pharmaceutical drugs is binding proteins.23),24) Using FG beads, in 2010 we called target deconvolution. There are several meth- identified cereblon (CRBN) as the sole direct target ods for achieving target deconvolution, including responsible for thalidomide teratogenicity.25) Various affinity purification using ligand-immobilized affinity researchers have subsequently investigated the role matrices, photoaffinity labeling, cellular thermal shift of CRBN in the effects of thalidomide. CRBN is assay, activity-based protein profiling, and drug No. 6] Thalidomide drug mechanisms 191 affinity responsive target stability analysis.33) Among FG beads, which avoids centrifugation, and non- these, we employed affinity purification and have specific background is also reduced using affinity been developing new affinity matrices for more than purification. SG and FG beads are currently pro- 30 years. Agarose is conventionally used as an affinity duced by Tamagawa Seiki Co., Ltd, and they are matrix, and in 1986 Tjian and colleagues identified commercially available. We used these beads for transcription factor Sp1, which binds to a specific isolating various target proteins of pharmaceutical DNA sequence, using DNA-immobilized agarose drugs and other bioactive metabolites.35)–45) beads.34) This ground-breaking discovery demon- fi strated the power of the purification technique for Identi cation of a primary direct target isolating ligand-specific binding proteins. However, of thalidomide using FG beads numerous non-specific proteins tend to interact with Thalidomide is composed of two parts: a hydrophobic compounds present in this matrix, phthalimide ring and a glutarimide ring. We synthe- including the hydrophobic thalidomide, and this is sized thalidomide derivative FR259625, which has a partially why target deconvolution failed for a long carboxylic acid group, and covalently attached it time for this molecule. Therefore, we developed non- through this group to amino groups on FG beads porous, physically stable matrices that were small (Fig. 2B). Using the resulting thalidomide-immobi- and highly dispersive, with surfaces that tend not to lized FG beads, we attempted to isolate target bind proteins non-specifically, and it is easy to modify proteins from various cell extracts (Fig. 2C), and the reactive groups for drug fixation because these managed to purify two proteins with molecular stable matrices are tolerant
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