{"id":3352,"date":"2023-08-31T04:28:49","date_gmt":"2023-08-31T09:28:49","guid":{"rendered":"https:\/\/www.bocsci.com\/blog\/?p=3352"},"modified":"2023-08-31T04:28:50","modified_gmt":"2023-08-31T09:28:50","slug":"thalidomide-analogs-and-other-crbn-ligands-in-protacs","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/thalidomide-analogs-and-other-crbn-ligands-in-protacs\/","title":{"rendered":"Thalidomide Analogs\u00a0and Other CRBN Ligands in\u00a0PROTACs"},"content":{"rendered":"\n

History of <\/a><\/strong>T<\/strong><\/strong>halidomide<\/strong><\/strong><\/a><\/strong><\/h2>\n\n\n\n

During the 1950s-1960s, thalidomide was widely used as an antiemetic for pregnant women, leading to a tragic outcome with thousands of cases of malformed babies. However, in 1965, Israeli doctors discovered that thalidomide could treat skin lesions in patients with leprosy. In 1997, the FDA approved thalidomide for treating acute erythema nodosum leprosum. In 2006, the FDA also approved thalidomide for the indication of multiple myeloma. The question remains: How does thalidomide cause birth defects, and why can it also treat cancer?<\/p>\n\n\n\n

In 2010, Handa et al<\/em>. proposed that thalidomide acts on CRBN in Science<\/em>, and in 2014, Fischer et al<\/em>. reported thalidomide’s interaction with CRBN in Nature<\/em>, finally uncovering the mystery behind the drug. However, even in late-stage cancer patients, thalidomide’s use presented significant problems due to its teratogenic side effects, necessitating close patient monitoring during treatment. Thus, due to thalidomide’s toxicity and antitumor activity, researchers attempted to develop safer and more effective thalidomide analogs.<\/p>\n\n\n\n

As drug development progressed, researchers discovered many optimized thalidomide analogs that could serve not only as molecular glues for various diseases but also as part of proteolysis-targeting chimeras (PROTACs)<\/a> for disease treatment.<\/p>\n\n\n\n

<\/a>Thalidomide<\/strong><\/strong><\/a> and its Analogs<\/strong><\/strong><\/h2>\n\n\n\n

Thalidomide is a racemic mixture of R-(+)- and S-(-)-configurations (Figure 1), where the R-configuration exhibits sedative effects and the S-configuration leads to teratogenic effects, causing the birth of thousands of infants with severe developmental abnormalities.<\/p>\n\n\n

\n
\"Structures<\/a>
Figure 1. Structures of the two configurations of thalidomide<\/figcaption><\/figure><\/div>\n\n\n

Thalidomide and its analogs are referred to as cereblon (CRBN) E3 ligase modulators (CELMoDs) or immunomodulatory drugs (IMiDs). They bind to CRBN, which forms an E3 ubiquitin ligase complex (CRL4) with DDB1 (damaged DNA binding protein 1), Cul4A (Cullin 4A), and ROC1. Through further development, pomalidomide<\/a> emerged as the first marketed thalidomide analog. Thalidomide and its analogs can function as molecular glues by binding to CRBN, which serves as a substrate receptor and binds to several proteins, promoting their ubiquitination and proteasome-dependent protein degradation<\/a>, such as CK1-\u03b1, Ikaros (IKZF1)\/Aiolos (IKZF3), GSPT1, and more (Figure 2).<\/p>\n\n\n

\n
\"Molecular<\/a>
Figure 2. Molecular glue action of CRBN ligand. (Fischer, 2014)<\/figcaption><\/figure><\/div>\n\n\n

CRBN ligands like thalidomide analogs can also be part of PROTACs, recruiting the E3 ligase CRBN to target proteins and promoting their degradation (Figure 3).<\/p>\n\n\n

\n
\"Degradation<\/a>
Figure 3. Degradation of target protein using a CRBN ligand as part of a PROTAC. (Gasic, 2020)<\/figcaption><\/figure><\/div>\n\n\n

Clinical Progress of Thalidomide and its Analogs<\/strong><\/strong><\/h2>\n\n\n\n

Apart from FDA approvals for treating acute erythema nodosum leprosum and multiple myeloma, thalidomide is being investigated for other indications, such as its role in treating advanced gastric cancer liver metastasis. Clinical trials are ongoing for CC-122, a novel CELMoD for lymphoma treatment, CC220 and CC92480 for refractory multiple myeloma, and CC90009 for acute myeloid leukemia. CC-90009 drives the interaction between GSPT1 and CRBN, leading to GSPT1’s proteasome-dependent degradation. CC-90009-AML-001 is a Phase 1 open-label, dose-escalation and expansion study targeting relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome patients (NCT02848001).<\/p>\n\n\n\n

Iberdomide<\/a> (CC-220) is an investigational CRBN inhibitor that induces degradation of transcription factors Aiolos and Ikaros, inhibiting multiple myeloma cell growth in vitro. Iberdomide has progressed to multiple clinical trials for different indications, including relapsed\/refractory multiple myeloma (Phase 2), non-Hodgkin lymphoma (Phase 1), and systemic lupus erythematosus (Phase 2).<\/p>\n\n\n\n

Moreover, efforts are underway to combine bb2121 with CC-220 and low-dose dexamethasone. CC-122, an IMiD derivative, enhances the degradation of IKZF1 and IKZF3 compared to thalidomide but doesn’t affect CK1. Multiple clinical trials are evaluating CC-122 alone or in combination. Mezigdomide<\/a> (CC-99282) induces degradation of IKZF1 and IKZF3 through CRBN E3 ligase binding and is also undergoing clinical trials.<\/p>\n\n\n\n

KPG-818, a novel oral small-molecule CRBN modulator, is being evaluated for safety, pharmacokinetics, and preliminary clinical activity in relapsed\/refractory multiple myeloma (MM) and other hematologic malignancies.<\/p>\n\n\n\n

TQB3820, a new CRBN modulator, has entered Phase 1 clinical trials to evaluate its tolerability and pharmacokinetics in relapsed\/refractory MM and indolent B-cell non-Hodgkin lymphoma patients.<\/p>\n\n\n\n

CRBN Ligands – Phenyl Dihydrouracil<\/strong> D<\/strong>erivatives<\/strong><\/h2>\n\n\n\n

In addition to the ongoing clinical development of CRBN inhibitors, researchers are exploring various types of CRBN inhibitory compounds. Recently, Tang et al.<\/em>\u00a0reported on Phenyl Dihydrouracil derivatives\u00a0as CRBN ligands in J Med Chem<\/em>. Traditional CRBN ligands used for PROTAC design are mostly Glutarimides, such as thalidomide, lenalidomide, and pomalidomide, which often possess a chiral center and are prone to racemization. In contrast, Phenyl Dihydrouracil derivatives do not have chiral issues.<\/p>\n\n\n

\n
\"Typical<\/a>
Figure 4. Typical structure of the novel CRBN ligand3<\/sup><\/figcaption><\/figure><\/div>\n\n\n

PROTACs are currently a hot topic in research, requiring recruitment of E3 ligases to target proteins. Common E3 ligases include VHL, CRBN, and MDM2. Compared to VHL ligands, CRBN ligands are smaller and have better drug-like properties. Therefore, CRBN ligands are favored for PROTAC design. Two prominent PROTAC molecules, ARV-471 and ARV-110, are currently in Phase 2 clinical trials for treating breast cancer and prostate cancer, respectively. Both utilize CRBN ligands, namely pomalidomide<\/a> and <\/a>lenalidomide<\/a>.<\/p>\n\n\n\n

Apart from pomalidomide and lenalidomide, researchers are now designing and synthesizing PROTACs using a novel CRBN ligand structure known as phenyl dihydrouracil derivatives. For example, Novartis published a patent (WO2021053495A1) demonstrating the versatility of such CRBN ligands. These ligands have been used as part of degraders for BTK, CSK, ABL2, EPHA4, YES1, TNNI3K, and others. As shown in the figure below, PROTACs targeting BTK<\/a> and BRD9 utilize 3-substituted phenyl dihydrouracil, which differs from Tang et al<\/em>.’s choice of 1,2,3-trisubstitution. Their approach achieved excellent BRD9 or BTK degradation.<\/p>\n\n\n

\n
\"PROTACs<\/a>
Figure 5. PROTACs targeting BRD9 and BTK3<\/sup><\/figcaption><\/figure><\/div>\n\n\n

Jamie et al<\/em>. reported the synthesis of a series of PROTACs targeting LCK using 2-substituted <\/a>phenyl dihydrouracil. Compounds like SJ34739 and SJ43489 demonstrated good activity and avoided degradation of neo-substrates such as GSPT1, IKZF1, and CK1\u03b1.<\/p>\n\n\n

\n
\"PROTACs<\/a>
Figure 6. PROTACs targeting LCK3<\/sup><\/figcaption><\/figure><\/div>\n\n\n

Beigene has also used these CRBN ligands to synthesize PROTACs targeting EGFR<\/a> and BTK. Their patent indicates a preference for 1,4-disubstitution, but there are also 1,2,4-substituted examples, often with fluorine, chlorine, methyl, or methoxy at position 2. These compounds efficiently degrade EGFR or BTK proteins.<\/p>\n\n\n

\n
\"PROTACs<\/a>
Figure 7. PROTACs targeting BTK and EGFR3<\/sup><\/figcaption><\/figure><\/div>\n\n\n

<\/a>Arvinas and C4 Therapeutics have also utilized phenyl dihydrouracil derivatives as CRBN ligands. Arvinas has employed them in PROTACs for degrading RAF proteins, as seen in PROTACs primarily using 1,2,4-trisubstitution phenyl dihydrouracil, with a preference for fluorine substitution at position 2, as described in patent WO 2022047145A1. In contrast, C4, in their patent WO2021127561A1, mostly utilizes PROTACs with 1,3,4-trisubstitution phenyl dihydrouracil, often substituting fluorine or chlorine at position 3, targeting EGFR degradation. While these two patents do not provide specific values, the degradation DC50 for both cases is below 100 nM.<\/p>\n\n\n

\n
\"PROTACs<\/a>
Figure 8. PROTACs targeting RAF and EGFR3<\/sup><\/figcaption><\/figure><\/div>\n\n\n

<\/a>The inclusion of phenyl dihydrouracil derivatives enriches the CRBN ligand library and facilitates PROTAC design. However, the clinical applications of these PROTACs still require further validation.<\/p>\n\n\n\n

References:<\/p>\n\n\n\n

    \n
  1. Fischer, E. S., et al.<\/em>, Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide, Nature<\/em>, 2014, 512<\/em>(7512):49-53.<\/li>\n\n\n\n
  2. Gasic, I., <\/a>et al.<\/em>, Tubulin Resists Degradation by Cereblon-Recruiting PROTACs, Cells, 2020, 9, 1083.<\/li>\n\n\n\n
  3. Xie, H., et al.<\/em>, Development of Substituted Phenyl Dihydrouracil as the Novel Achiral Cereblon Ligands for Targeted Protein Degradation, J. Med. Chem.<\/em>, 2023, 66<\/em>, 4, 2904-2917.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

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