The protein cereblon (CRBN) is a substrate receptor of the cullin 4-really interesting new gene (RING) E3 ubiquitin ligase complex CRL4CRBN. Targeting CRBN mediates selective protein ubiquitination and subsequent degradation via the proteasome. This review describes novel thalidomide analogs, immunomodulatory drugs, also known as CRBN E3 ubiquitin ligase modulators or molecular glues (avadomide, iberdomide, CC-885, CC-90009, BTX-1188, CC-92480, CC-99282, CFT7455, and CC-91633), and CRBN-based proteolysis targeting chimeras (PROTACs) with increased efficacy and potent activity for application in hematologic malignancies. Both types of CRBN-binding drugs, molecular glues, and PROTACs stimulate the interaction between CRBN and its neosubstrates, recruiting target disease-promoting proteins and the E3 ubiquitin ligase CRL4CRBN. Proteins that are traditionally difficult to target (transcription factors and oncoproteins) can be polyubiquitinated and degraded in this way. The competition of CRBN neosubstrates with endogenous CRBN-interacting proteins and the pharmacology and rational combination therapies of and mechanisms of resistance to CRL4CRBN modulators or CRBN-based PROTACs are described.
- MeSH
- hematologické nádory * farmakoterapie MeSH
- lidé MeSH
- proteasy * chemie genetika metabolismus MeSH
- transkripční faktory metabolismus MeSH
- ubikvitinace MeSH
- ubikvitinligasy chemie genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Incorrectly expressed or mutated proteins associated with hematologic malignancies have been generally targeted by chemotherapy using small-molecule inhibitors or monoclonal antibodies. But the majority of these intracellular proteins are without active sites and antigens. PROTACs, proteolysis targeting chimeras, are bifunctional molecules designed to polyubiquitinate and degrade specific pathological proteins of interest (POIs) by hijacking the activity of E3-ubiquitin ligases for POI polyubiquitination and subsequent degradation by the proteasome. This strategy utilizes the ubiquitin-proteasome system for the degradation of specific proteins in the cell. In many cases, including hematologic malignancies, inducing protein degradation as a therapeutic strategy offers therapeutic benefits over classical enzyme inhibition connected with resistance to inhibitors. Limitations of small-molecule inhibitors are shown. PROTACs can polyubiquitinate and mark for degradation of "undruggable"proteins, e.g. transcription factor STAT3 and scaffold proteins. Today, this technology is used in preclinical studies in various hematologic malignancies, mainly for targeting drug-resistant bromodomain and extraterminal proteins and Bruton tyrosine kinase. Several mechanisms limiting selectivity and safety of PROTAC molecules function are also discussed.
- MeSH
- hematologické nádory farmakoterapie metabolismus MeSH
- leukemie farmakoterapie metabolismus MeSH
- lidé MeSH
- lymfom farmakoterapie metabolismus MeSH
- objevování léků * MeSH
- proteasomový endopeptidasový komplex metabolismus MeSH
- proteolýza účinky léků MeSH
- protinádorové látky chemie farmakologie MeSH
- ubikvitinace účinky léků MeSH
- ubikvitinligasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Inhibice proteinů nízkomolekulárními inhibitory je omezena na enzymy a receptory, které tvoří přibližně 25 % lidského proteomu. Většina proteinů, jako jsou transkripční faktory, strukturální proteiny, regulační proteiny a proteiny bez funkce enzymu, je nedostupná (undruggable) pro inhibiční molekuly. Během posledních 20 let byl vyvinut postup založený na mechanismu indukované degradace proteinů, využívající polyubikvitinaci a rozklad v proteazomech pomocí PROTACs (proteolysis-targeting chimeras). Dvoufunkční molekuly PROTACs jsou složeny ze specifického ligandu pro protein určený k degradaci, spojky (linker) a ze specifického ligandu pro E3 ubikvitinligázu využívanou v polyubikvitinaci cílového proteinu pro jeho následnou degradaci v proteazomech. Uvedené dvoufunkční molekuly byly experimentálně úspěšně použity k degradaci řady proteinů, které hrají důležité funkce v patogenezi hematologických malignit a jsou předmětem tohoto souhrnného článku.
Inhibition of proteins with small-molecule inhibitors is restricted to receptors and enzymes which make up approximately 25% of the human proteome. The majority of proteins such as transcription factors, scaffolding proteins, regulatory proteins and non-enzymatic proteins are difficult (“undruggable“) targets for small-molecule inhibitors. In the past 20 years, new procedures have been developed based on the mechanism of inducible protein degradation that exploits polyubiquitination and degradation in proteasomes using proteolysis targeting chimeras (PROTACs). Bifunctional molecules (PROTACs) are composed of specific ligand for the protein of interest connected via a linker to a specific ligand for E3 ubiquitin ligase used in protein of interest polyubiquitination and its subsequent degradation in proteasomes. The presented bifunctional molecules have been successfully used experimentally in degradation of many proteins of interest that have important functions in the pathogenesis of haematological malignancies and are the subject of this review.
- Klíčová slova
- chimera pro cílenou proteolýzu (PROTAC), proteazom, E3 ubikvitinligáza,
- MeSH
- cílená molekulární terapie metody MeSH
- inhibitory enzymů farmakologie MeSH
- lékové transportní systémy * MeSH
- lidé MeSH
- objevování léků MeSH
- proteolýza * účinky léků MeSH
- racionální návrh léčiv MeSH
- ubikvitin terapeutické užití MeSH
- Check Tag
- lidé MeSH
Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.
- MeSH
- imunomodulace účinky léků MeSH
- lidé MeSH
- lymfom farmakoterapie patologie MeSH
- myelodysplastické syndromy farmakoterapie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Transformační růstový faktor beta (TGF-β) je cytokin pojmenovaný podle schopnosti transformovat normální fibroblasty v kultuře. Později bylo zjištěno, že TGF-β inhibuje růst epiteliálních a lymfoidních buněk. Rodina TGF-β zahrnuje TGF-β1, TGF-β2, TGF-β3, aktiviny A a B, nodal, myostatin, různé růstové diferenciační faktory (GDF), kostní morfogenetické proteiny (BMP) a anti-Müllerian hormon (AMH). Velký počet těchto ligand (více než třicet) se váže k daleko menšímu počtu specifických transmembránových receptorů na povrchu buněk a vnitrobuněčných signálních molekul. Aktivace receptorů pro TGF-β a jejich fosforylace je spojena s myelosupresí a neefektivní erytropoézou u myelodysplastického syndromu (MDS). Anémie je převládající příčinou špatné kvality života a úmrtnosti pacientů s nízkorizikovým MDS (LR-MDS). Lenalidomid byl schválen jen pro léčbu nízkorizikových del(5q) MDS po selhání účinku látek stimulujících erytropoézu (ESA), označovaných také jako erytropoézu stimulující proteiny (ESP). Ostatní pacienti s LR-MDS bez této delece jsou odkázáni po selhání účinku ESP na transfuze červených krvinek. Cílená inhibice signální dráhy TGF-β v preklinických a klinických studiích ukázala slibné výsledky. Sotatercept a jeho pozdější a účinější analog luspatercept stimulovaly erytropoézu u žen po menopauze léčených na osteoporózu a byly také účinné u specifické skupiny pacientů s MDS s prstenčitými sideroblasty, kteří přestali reagovat na ESP. Luspatercept je první inhibitor dráhy TGF-β, určený pro stimulaci pozdní fáze erytroidní diferenciace a zmírnění či odstranění anémie, který je těsně před schválením na základě slibných výsledků studií fáze III MEDALIST u LR-MDS a BELIEVE u β-thalasemie.
Transforming growth factor (TGF)-β is a cytokine originally named for its ability to transform normal fibroblasts in culture. TGF-β was subsequently found to inhibit growth of epithelial and lymphoid cells. The cellular response to TGF-β depends on the cell type and cell microenvironment. The TGF-β family includes TGF-β1, TGF-β2, TGF TGF-β3, activins A and B, nodal, myostatin, different growth differentiation factors (GDFs), the bone morphogenetic proteins (BMPs) and the anti-Műllerian hormone (AMH). More than thirty of these ligands use a far smaller number of receptors and down-stream intracellular signalling molecules. TGF-β receptor activation and phosphorylation is associated with the myelosuppression and ineffective erythropoiesis in myelodysplastic syndrome (MDS). Anaemia is the predominant cause of poor quality of life and morbidity in patients with lower-risk MDS (LR-MDS). Lenalidomide was approved only for the treatment of del(5q) MDS after failure of erythropoiesis stimulating agents (ESAs), also known as erythropoiesis stimulating proteins (ESPs). Other patients with LR-MDS have very limited therapy options after failure of ESPs and are dependent on red blood cell transfusions. Targeted inhibition of the TGF-β signalling pathway in preclinical and clinical studies showed promising results. Sotatercept and its later analogue luspater-cept stimulated erythropoiesis in postmenopausal women with osteoporosis and were also efficient in a specific group of MDS patients with ring sideroblasts who had lost their response to ESPs. Luspatercept is the first TGF-βpathway inhibitor intended for the stimulation of late stage of erythroid differentiation and for the treatment of anaemia awaiting approval on the basis of promising results of phase III studies, namely MEDALIST in RL-MDS and BELIEVE in transfusion-dependent β-thalassemia.
- Klíčová slova
- prstenčité sideroblasty, signální dráha TGF-β, sotatercept, luspatercept, galunisertib, vactosertib,
- MeSH
- anemie farmakoterapie MeSH
- erythropoetin farmakologie terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- myelodysplastické syndromy * farmakoterapie MeSH
- protokoly protinádorové léčby MeSH
- růstové diferenciační faktory farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
2 svazky : grafy ; 30 cm
Chceme přispět k objasnění mechanismu patogeneze 5q – syndromu studiem důležitých transkripčních faktorů, EKLF (“erythroid Krüppel-like factor“, označovaný také KLF1), Fli1 (“Friend leukemia integration 1“) a GATA1, které se kromě řady dalších faktorů podílejí na diferenciaci společné progenitorové buňky MEP (“megakaryocyte-erythroid progenitor“) do erytroidní nebo megakaryocytární řady. Expresi uvedených a dalších genů, potenciálně důležitých v tomto mechanismu, chceme zkoumat metodou kvantitativní TaqMan RT-PCR v reálném čase na pacientech MDS s 5q- syndromem ve srovnání s MDS o nízkém riziku a s normálním chromozomem 5 a se zdravými kontrolami na separovaných buňkách kostní dřeně a periferní krve. Naším druhým záměrem je přispět k objasnění mechanismu účinku účinné imunomodulační látky lenalidomidu u pacientů s 5q- syndromem ve srovnání s MDS o nízkém riziku a s normálním chromozomem 5. Budou analyzovány mutace EKLF, které mohou významně ovlivnit odpověď na lenalidomid.; We want to contribute to further understanding of the 5q- syndrome pathogenesis mechanism by the study of the important transcription factors, EKLF (erythroid Krüppel like factor, also called KLF1), Fli1 (Friend leukemia virus integration 1) and GATA1, which take part together with other factors on the differentiation of common MEP progenitor cell into erythroid or megakaryocytic line. The expression of these and other important genes in this mechanism will be analysed in separated bone marrow and blood cells of patients MDS with 5q- syndrom in comparison with low-risk MDS with normal chromosome 5 and with healthy controls by TaqMan real-time PCR. Our second aim is to contribute to the understanding of the mechanism of the effective agent lenalidomide in patients with 5q- syndrome in comparison with low-risk MDS with normal chromosome 5. Mutations of EKLF, which can significantly affect lenalidomide treatment, will be also detected.
Multiple myeloma (MM) remains an incurable disease, at least for the big majority of patients, in spite of the great progress with new drugs in the last years. New treatment strategies are needed to improve the outcome of patients. NF-κB activation in MM is caused by mutations in the factors involved in the NF-κB pathways contributing to their dysregulation and by signals from the bone marrow microenvironment. Agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents. Bortezomib was the first approved member of a new class of anti-MM agents, the proteasome inhibitors. At least, five proteasome inhibitors of the next generation with greater efficacy (carfilzomib, marizomib (salinosporamide A, NPI-0052), threonine boronic acid-derived proteasome inhibitor CEP-18770, the peptide-semicarbazone S-2209, the tripeptide mimetic BSc2118, and MLN9708/2238) have been recently tested in preclinical models of MM. Carfilzomib has been recently approved for the treatment of patients with MM who have received at least two prior therapies, including bortezomib and immunomodulatory derivatives (IMiDs, thalidomide, lenalidomide or pomalidomide). More specific IκB kinase inhibitors were also used in preclinical studies. The analysis of MM genomes revealed also mutations in genes for histone methyltransferases (HMTases), histone demethylase (UTX) and serine/threonine protein kinase BRAF. Aberrant histone 3 lysine 27 trimethylation (H3K27me3) by mutant HMTases or UTX induces overexpression of the homeobox A9 (HOXA9) gene. HOXA9 is normally expressed in primitive bone marrow cells and is silenced when cells differentiate. HOXA9 is a MM oncogene and targeting of its expression by histone deacetylases inhibitors or by a phosphoinositide 3-kinase (PI3K) inhibitors through an epigenetic mechanism involving H3K27me3. Mutant BRAF kinase small-molecule, ATP-competitive, a highly selective, potent and orally bioavailable inhibitors (GDC-0879, PLX 4032 and PLX 4720) are already under investigation and PLX 4032 is in phase II and phase III clinical trials. Two key signaling pathways involved in the regulation of MM cell growth are the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways and their inhibition are anti-proliferative and pro-apoptotic and can overcome the development of resistance to common drugs.
- MeSH
- cílená molekulární terapie MeSH
- epigenomika MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie genetika metabolismus patologie MeSH
- NF-kappa B genetika metabolismus MeSH
- signální transdukce účinky léků MeSH
- stanovení celkové genové exprese MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
