Cereblon E3 ligase modulators, also known as immunomodulatory imide drugs (IMiDs) or CELMoDs, are a class of immunomodulatory drugs (drugs that adjust immune responses) containing an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, mezigdomide, iberdomide, and golcadomide). These drugs may also be referred to as 'Cereblon modulators'. Cereblon (CRBN) is the protein targeted by this class of drugs.
The name "IMiD" alludes to both "IMD" for "immunomodulatory drug" and the forms imide, imido-, imid-, and imid.
The development of analogs of thalidomide was precipitated by the discovery of the anti-angiogenic and anti-inflammatory properties of the drug yielding a new way of fighting cancer as well as some inflammatory diseases after it had been banned in 1961. The problems with thalidomide included teratogenic side effects, high incidence of other adverse reactions, poor solubility in water and poor absorption from the intestines.
In 1998 thalidomide was approved by the U.S. Food and Drug Administration (FDA) for use in newly diagnosed multiple myeloma (MM) under strict regulations. This has led to the development of a number of analogs with fewer side effects and increased potency which include lenalidomide and pomalidomide, which are currently marketed and manufactured by Celgene.
History
Thalidomide was originally released in the Federal Republic of Germany (West Germany) under the label of Contergan on October 1, 1957, by Chemie Grünenthal (now Grünenthal). The drug was primarily prescribed as a sedative or hypnotic, but it was also used as an antiemetic for morning sickness in pregnant women. The drug was banned in 1961 after its teratogenic properties were observed. The problems with thalidomide were, aside from the teratogenic side effects, both high incidence of other adverse reactions along with poor solubility in water and absorption from the intestines.Reversal of Fortune: How a Vilified Drug Became a Life-saving Agent in the "War" Against Cancer - Onco'Zine - The International Oncology Network (November 30, 2013) Adverse reactions include peripheral neuropathy in large majority of patients, constipation, thromboembolism along with dermatological complications.
Four years after thalidomide was withdrawn from the market for its ability to induce severe birth defects, its anti-inflammatory properties were discovered when patients with erythema nodosum leprosum (ENL) used thalidomide as a sedative and it reduced both the clinical signs and symptoms of the disease. Thalidomide was discovered to inhibit tumour necrosis factor-alpha (TNF-α) in 1991 (5a Sampaio, Sarno, Galilly Cohn and Kaplan, JEM 173 (3) 699–703, 1991) . TNF-α is a cytokine produced by macrophages of the immune system, and also a mediator of inflammatory response. Thus the drug is effective against some inflammatory diseases such as ENL (6a Sampaio, Kaplan, Miranda, Nery..... JID 168 (2) 408-414 2008). In 1994 Thalidomide was found to have anti-angiogenic activity and anti-tumor activity which propelled the initiation of clinical trials for cancer including multiple myeloma. The discovery of the anti-inflammatory, anti-angiogenic and anti-tumor activities of thalidomide increased the interest of further research and synthesis of safer analogs.
Lenalidomide is the first analog of thalidomide which is marketed. It is considerably more potent than its parent drug with only two differences at a molecular level, with an added amino group at position 4 of the phthaloyl ring and removal of a carbonyl group from the phthaloyl ring. Development of lenalidomide began in the late 1990s and clinical trials of lenalidomide began in 2000. In October 2001 lenalidomide was granted orphan status for the treatment of MM. In mid-2002 it entered phase II and by early 2003 phase III. In February 2003 FDA granted fast-track status to lenalidomide for the treatment of relapsed or refractory MM. In 2006 it was approved for the treatment of MM along with dexamethasone and in 2007 by European Medicines Agency (EMA). In 2008, phase II trial observed efficacy in treating Non-Hodgkin's lymphoma.
Pomalidomide (3-aminothalidomide) was the second thalidomide analog to enter the clinic being more potent than both of its predecessors. First reported in 2001, pomalidomide was noted to directly inhibit myeloma cell proliferation and thus inhibiting MM both on the tumor and vascular compartments. This dual activity of pomalidomide makes it more efficacious than thalidomide both in vitro and in vivo. This effect is not related to TNF-α inhibition since potent TNF-α inhibitors such as rolipram and pentoxifylline did not inhibit myeloma cell growth nor angiogenesis. Upregulation of interferon gamma, IL-2 and IL-10 have been reported for pomalidomide and may contribute to its anti-angiogenic and anti-myeloma activities.
Development The thalidomide molecule is a synthetic derivative of glutamic acid and consists of a glutarimide ring and a phthaloyl ring (Figure 5). Its IUPAC name is 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione and it has one chiral center After thalidomide's selective inhibition of TNF-α had been reported, a renewed effort was put in thalidomide's clinical development. The clinical development led to the discovery of new analogs which strived to have improved activities and decreased side effects.
Clinically, thalidomide has always been used as a racemate. Generally the S-isomer is associated with the infamous teratogenic effects of thalidomide and the R-isomer is devoid of the teratogenic properties but conveys the sedative effects, however this view is highly debated and it has been argued that the animal model that these different R- and S-effects were seen in was not sensitive to the thalidomide teratogenic effects. Later reports in rabbits, which is a sensitive species, unveiled teratogenic effects from both isomers. Moreover, thalidomide enantiomers have been shown to be interconversed in vivo due to the acidic chiral hydrogen in the asymmetric center (shown, for the EM-12 analog, in Figure 3), so the plan to administer a purified single enantiomer to avoid the teratogenic effects will most likely be in vain.
Development of lenalidomide and pomalidomide
One of the analogs of interest was made by isoindolinone replacement of the phthaloyl ring. It was given the name EM-12 (Figure 3). This replacement was thought to increase the bioavailability of the substance because of increased stability. The molecule had been reported to be an even more potent teratogenic agent than thalidomide in rats, rabbits and monkeys. Additionally, these analogs are more potent inhibitors of angiogenesis than thalidomide. As well, the amino-thalidomide and amino-EM-12 were potent inhibitors of TNF-α. These two analogs later got the name lenalidomide, which is the EM-12 amino analog, and pomalidomide, the thalidomide amino analog.
Medical use The primary use of IMiDs in medicine is in the treatment of cancers and autoimmune diseases (including one that is a response to the infection leprosy). Indications for these agents that have received regulatory approval include: Myelodysplastic syndrome, a precursor condition to acute myeloid leukaemia Erythema nodosum, a complication of leprosy Multiple myeloma Follicular lymphoma
Off-label indications for which they seem promising treatments include: Hodgkin's lymphoma Light chain-associated (AL) amyloidosis Primary myelofibrosis (PMF) Acute myeloid leukaemia (AML) Prostate cancer Metastatic renal cell carcinoma (mRCC) Mantle cell lymphoma
Thalidomide Thalidomide has been approved by the FDA for ENL and MM in combination with dexamethasone. EMA has also approved it to treat MM in combination with prednisone and/or melphalan. Orphan indications by the FDA include graft-versus-host disease, mycobacterial infection, recurrent aphthous ulcers, severe recurrent aphthous stomatitis, primary brain malignancies, AIDS-associated wasting syndrome, Crohn's disease, Kaposi's sarcoma, myelodysplastic syndrome, and hematopoietic stem cell transplantation.
Lenalidomide Lenalidomide is approved in nearly 70 countries, in combination with dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. It is also approved in combination with rituximab for the treatment of patients with follicular lymphoma who have received at least one prior therapy. Orphan indications include diffuse large B-cell lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma. Lenalidomide is also approved for transfusion-dependent anemia due to low or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities in the U.S., Canada, Switzerland, Australia, New Zealand, Malaysia, Israel and several Latin American countries, while marketing authorisation application is currently being evaluated in a number of other countries. Numerous clinical trials are already in the pipeline or being conducted to explore further use for lenalidomide, alone or in combination with other drugs. Some of these indications include acute myeloid leukemia, MALT lymphoma, Waldenström macroglobulinemia, lupus erythematosus, Hodgkin's lymphoma, myelodysplastic syndrome and more.
Pomalidomide Pomalidomide was submitted for FDA approval on April 26, 2012 and on 21 June it was announced that the drug would get standard FDA review. A marketing authorization application was filed to EMA 21 June 2012, where a decision could come as soon as early 2013. EMA has already granted pomalidomide an orphan designation for primary myelofibrosis, MM, systemic sclerosis, post-polycythaemia and post-essential thrombocythaemia myelofibrosis.
Adverse effects The major toxicities of approved IMiDs are peripheral neuropathy, thrombocytopenia, anaemia and venous thromboembolism. There may be an increased risk of secondary malignancies, especially acute myeloid leukaemia in those receiving IMiDs.
Teratogenicity Thalidomide's teratogenicity has been a subject of much debate and over the years numerous hypotheses have been proposed. Two of the best-known have been the anti-angiogenesis hypothesis and oxidative stress model hypothesis, with considerable experimental evidence supporting these two hypotheses regarding thalidomide's teratogenicity.
Recently, new findings have emerged that suggest a novel mechanism of teratogenicity. Cereblon is a 51 kDa protein localized in the cytoplasm, nucleus and peripheral membrane of cells in numerous parts of the body. It acts as a component of the E3 ubiquitin ligase, regulating various developmental processes, including embryogenesis, carcinogenesis and cell cycle regulation, through degradation (ubiquitination) of unknown substrates. Thalidomide has been shown to bind to cereblon, inhibiting the activity of the E3 ubiquitin ligase, resulting in accumulation of the ligase substrates and downregulation of fibroblast growth factor 8 (FGF8) and FGF10. This disrupts the positive feedback loop between the two growth factors, possibly causing both multiple birth defects and anti-myeloma effects.
Findings also support the hypothesis that an increase in the expression of cereblon is an essential element of the anti-myeloma effect of both lenalidomide and pomalidomide. Cereblon expression was three times higher in responding patients compared to non-responders and higher cereblon expression was also associated with partial or full response while lower expression was associated with stable or progressive disease.
Mechanism of action