Результаты поиска

Synthesis, structure-activity relationships, antitumor activities and mechanistic studies of ENL-degrading compounds.

Transcription cofactor ENL is a novel target for MLL-rearranged (MLL-r) leukemia and other blood cancers. We designed and synthesized several series of ENL-degrading compounds. Cereblon-recruiting, proteolysis targeting chimera (PROTAC) compounds 1-6 and 14 can efficiently degrade and deplete ENL with DC50 as low as 4.2 nM, but not its paralog AF9. Mechanistic studies showed that the lysine residues of ENL(173-190) are critical for selective ENL degradation. These compounds selectively inhibited proliferation of MLL-r leukemia and multiple myeloma cells with EC50s as low as 130 nM. Depletion o…

Novel MYH11::GLI3 fusion in ileal leiomyoma.

BACKGROUND: Leiomyomas of the gastrointestinal tract (GI) are benign smooth muscle neoplasms with limited genetic characterization. Molecula … signaling. CONCLUSION: This study reports, for the first time, the identification of a MYH11::GLI3 chimera in gastrointestinal leiomyoma, thereby expanding the molecular spectrum of these tumors. Deregulation of GLI3 may represent an alternative mechanism of Hedgehog pathway perturbation in this neoplasm. The frequency and clinical significance of GLI3-r …

Фармакологические цели IRF4 в качестве терапевтической стратегии для множественной миеломы.

Интерферонный нормативный коэффициент 4 (IRF4) представляет собой онкогенный коэффициент транскрипции (TF) в ряде гематологических магнатов. На сегодняшний день не разработано никаких фармакологических агентов, специально предназначенных для IRF4, в силу сложного характера адресной работы с ЦГ. Здесь мы впервые идентифицировали (S)-H1, папку IRF4, нацелив взаимодействие SPI1-IRF4 на интерферонный ассоциационный домен IRF4 с помощью скрининга с высокой производительностью. Затем мы успешно превратили наш папку в DIRF4-2, первый в классе протеолизирующий химера IRF4, связывая (S)-H1 с E3 лигами

Совпадение в аннотации оригинала
Interferon regulatory factor 4 (IRF4) is an oncogenic transcription factor (TF) in several hematological malignancies. To date, no pharmacol … ening. Next, we successfully turned our binder into dIRF4-2, a first-in-class proteolysis-targeting chimera of IRF4, by linking (S)-H1 to E3 ligase ligands of cereblon. dIRF4-2 can induce highly selective proteasomal degradation of IRF4 and has strong cytotoxic effects in all multiple myeloma lines evaluated in vitro. Our study showcases methodology to ef …

Discovery of Rigid Linker-Based IRAK4 PROTACs with Improved Metabolic Stability for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target for inflammatory diseases. However, solely inhibiting IRAK4 kinase activity fails to fully block inflammatory signaling, resulting in limited efficacy. Herein, we describe the design and synthesis of novel IRAK4 degraders based on a proteolysis-targeting chimera (PROTAC) strategy. The preferred compound, FIP22, effectively degraded cellular IRAK4 with a DC50 of 3.2 nM, 115-fold higher than the lead compound DE5. Mechanistically, FIP22 induces the ubiquitin-proteasome system by forming an IRAK4-FIP22-CRBN terna…

A recombinant chimeric antigen constructed with B-cell epitopes from Mycobacterium leprae hypothetical proteins is effective for the diagnosis of leprosy.

The diagnosis if leprosy is difficult, as it requires clinical expertise and sensitive laboratory tests. In this study, we develop a serological test for leprosy by using bioinformatics tools to identify specific B-cell epitopes from Mycobacterium leprae hypothetical proteins, which were used to construct a recombinant chimeric protein, M1. The synthetic peptides were obtained and showed good reactivity to detect leprosy patients, although the M1 chimera have showed sensitivity (Se) and specificity (Sp) values higher than 90.0% to diagnose both paucibacillary (PB) and multibacillary (MB) lepro…

Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle.

Troponin regulates the calcium-mediated activation of skeletal muscle. Muscle weakness in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy occurs from diminished neuromuscular output. The first direct fast skeletal troponin activator, tirasemtiv, amplifies the response of muscle to neuromuscular input. Tirasemtiv binds selectively and strongly to fast skeletal troponin, slowing the rate of calcium release and sensitizing muscle to calcium. We report the solution NMR structure of tirasemtiv bound to a fast skeletal troponin C-troponin I chimera. The structure reveals t…

Dynamic folding modulation generates FGF21 variant against diabetes.

Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate f … pin and further overall protein stability. To modulate folding dynamics, we designed an FGF21-FGF19 chimera, FGF21SS . As expected, FGF21SS shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21SS shows its better insulin sensitivity, reduced inflammation in 3T3-L1 adipocytes, and lower blood glucose a …

Studies examining the relationship between the chemical structure of protoxin II and its activity on voltage gated sodium channels.

The aqueous solution structure of protoxin II (ProTx II) indicated that the toxin comprises a well-defined inhibitor cystine knot (ICK) backbone region and a flexible C-terminal tail region, similar to previously described NaSpTx III tarantula toxins. In the present study we sought to explore the structure-activity relationship of the two regions of the ProTx II molecule. As a first step, chimeric toxins of ProTx II and PaTx I were synthesized and their biological activities on Nav1.7 and Nav1.2 channels were investigated. Other tail region modifications to this chimera explored the effects of…

Adult metachromatic leukodystrophy treated by allo-SCT and a review of the literature.

Five patients with adult-onset metachromatic leukodystrophy (MLD) underwent allo-SCT. Conditioning was reduced in intensity and grafts were obtained from voluntary unrelated donors. All but one graft were depleted of T-lymphocytes. Patient age at transplantation varied from 18 to 29 (median, 27) years. Two patients rejected their graft and MLD progressed. The recipient of the unmanipulated graft converted to complete donor chimerism with normalization of arylsulphatase A (ARSA) levels. Despite ARSA normalization, he deteriorated. Another patient was a mixed chimera. Following escalated doses o…

Chimerism and multiple numerical chromosome imbalances in a spontaneously aborted fetus.

We report on a case of chimerism and multiple abnormalities of chromosomes 21, Xand Yin spontaneous abortion specimen. To the best our knowledge the present case is the first documented chimera in a spontaneously aborted fetus. The application of interphase fluorescence in situ hybridization (FISH) using chromosome enumeration and site-specific DNA probes showed trisomy X in 92 nuclei (23 %), tetrasomy X in 100 nuclei (25 %), pentasomy of chromosome X in 40 nuclei (10 %), XXY in 36 nuclei (9 %), XXXXXXYY in 12 nuclei (3 %), XXXXXYYYYY in 8 nuclei (2 %), trisomy 21 and female chromosome complem…

A Small-Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau.

Accumulation of hyperphosphorylated Tau (p-Tau) is a central driver of neurodegeneration in Alzheimer's disease (AD). Addressing the limitations of current therapeutics, we developed TP2, a small-molecule DEPhosphorylation-TArgeting Chimera (DEPTAC). TP2 is engineered to physically tether endogenous PP2A to Tau, facilitating targeted dephosphorylation. Mechanistically, TP2 induces ternary complex formation and potently reduces p-Tau in neurons. Systemic administration of TP2 in distinct tauopathy mouse models (P301L and AAV-hTau-N368) significantly lowered brain p-Tau levels, oligomers, and ne…

Targeted Degradation of Capsid by Host-Hijacking PROTAC Overcomes Drug Resistance.

The escalating prevalence of HIV-1 drug-resistant variants and the toxicity limitations of conventional antiretroviral therapies necessitate therapeutic strategies with novel mechanisms of action. This study focuses on HIV-1 capsid (CA), an essential replication-related viral protein. We developed CA-targeted proteolysis-targeting chimera (PROTAC) degraders by conjugating PF74-derived CA ligand IIA-4 with VHL E3 ligase ligand. Among these, VHL-3 exhibited potent anti-HIV-1 activity in MT-4 cells (EC50 = 3.0 ± 1.5 nM), a 300-fold improvement over PF74. Mechanistic studies confirmed VHL-3 dose- …

Discovery of LYA914, An Orally Bioavailable PROTAC Degrader Targeting the DNA Binding Domain of the Androgen Receptor for the Treatment of CRPC.

Prostate cancer is a common male malignancy. Although androgen deprivation therapy (ADT) is initially effective, it often leads to castration-resistant prostate cancer (CRPC) eventually. Second-generation androgen antagonists are the standard therapy for CRPC. However, resistance develops due to mutations or splice variants in the ligand binding domain (LBD) of the androgen receptor (AR). Therefore, the development of novel, efficient, and safe therapeutic agents for CRPC is of great significance. In this study, we designed and synthesized compound LYA914 as a proteolysis-targeting chimera (PR…

Engineering ultrapotent trivalent anticoagulants through hybridisation of salivary peptides from multiple haematophagous organisms.

Haematophagous organisms are a rich source of salivary anticoagulant polypeptides that exert their activity by blocking the catalytic site and one of two positively charged exosites on the host protease thrombin. Here, we describe a molecular engineering approach to hybridise post-translationally sulfated polypeptides from different blood-feeding organisms to enhance anticoagulant activity. This led to the discovery of a triply sulfated hybrid anticoagulant, XChimera, possessing fragments from flea, leech, and fly salivary polypeptides that exhibits femtomolar inhibitory activity against throm…

Discovery of a Novel Non-invasive AR PROTAC Degrader for the Topical Treatment of Androgenetic Alopecia.

Elevated expression levels and enhanced activity of androgen receptor (AR) proteins are key factors in the development of androgenetic alopecia (AGA). AR proteolysis-targeting chimera (PROTAC) degraders have shown therapeutic potential, but their poor skin permeability requires invasive delivery methods. In this study, we conducted a structure feature analysis to investigate the effects of different linkers and E3 ligands of AR PROTACs on skin retention properties and degradation potency. Among these, compound C6 was discovered with excellent skin retention properties and nanomolar level AR de…

Single-cell transcriptomics identifies perturbed molecular pathways in midbrain organoids using α-synuclein triplication Parkinson's disease patient-derived iPSCs.

Three-dimensional (3D) brain organoids provide a platform to study brain development, cellular coordination, and disease using human tissue. … profiles associated with synaptic signalling and cholesterol biosynthesis. Finally, we show a novel chimera organoid model from healthy and PD iPSCs allowing the study of DA neurons from different individuals within the same tissue.

Rational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation.

Protein degradation mediated by the proteolysis-targeting chimera (PROTAC) has emerged as an efficient strategy to accurately control intracellular protein levels. However, the development of PROTACs is limited by their systemic toxicity. Herein, we report a bioorthogonally activatable prodrug (BT-PROTAC) strategy to accurately control the activity of PROTACs. As a proof of concept, we introduced the highly reactive trans-cyclooctene into PROTAC molecule MZ1, the structure-acitivity relationships of which were well characterized previously, to construct the bioorthogonally activatable prodrug …

CD11c regulates late-stage T cell development in the thymus.

CD11c, also named integrin αX, has been deemed solely as a dendritic cell marker for decades while the delineation of its biological function was limited. In the current study, we observed in mice that CD11c deficiency led to a defect in T cell development, demonstrated by the loss of CD4+CD8+ double positive (DP) T cells, CD4+CD8-, and CD4-CD8+ single positive (SP) T cells in the thymus and less mature T cells in the periphery. By using bone marrow chimera, we confirmed that CD11c regulated T cell development in the thymus. We further showed that CD11c deficiency led to an accelerated apoptos…

Targeting BCL-XL in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition o … mbocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xe …

Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment.

Reprogramming known medicines for a novel target with activity and selectivity over the canonical target is challenging. By studying the bin … t RNA-targeting activity and decreasing potency against canonical RTK protein targets in cells, the chimera shifted selectivity for pre-miR-21 by 2500-fold, alleviating disease progression in mouse models of triple-negative breast cancer and Alport Syndrome, both caused by miR-21 overexpression. Thus, targeted degradation can dramatically improve selectiv …