1 596 122 BET PROTEINS: AN APPROACH TO FUTURE THERAPIES IN TRANSPLANTATION. IN ORDER TO DEVELOP NEW EFFICIENT THERAPIES FOR ORGAN TRANSPLANTATION, IT IS ESSENTIAL TO ACQUIRE A COMPREHENSIVE KNOWLEDGE OF THE MOLECULAR MECHANISMS AND PROCESSES, SUCH AS IMMUNE ACTIVATION, CHRONIC INFLAMMATION, AND FIBROSIS, WHICH LEAD TO REJECTION AND LONG-TERM GRAFT LOSS. RECENT EFFORTS HAVE SHED SOME LIGHT ON THE EPIGENETIC REGULATION ASSOCIATED WITH THESE PROCESSES. IN THIS CONTEXT, THE BROMO AND EXTRATERMINAL (BET) FAMILY OF BROMODOMAIN PROTEINS (BRD2, BRD3, BRD4, AND BRDT) HAVE EMERGED AS MAJOR EPIGENETIC PLAYERS, CONNECTING CHROMATIN STRUCTURE WITH GENE EXPRESSION CHANGES. THESE PROTEINS RECOGNIZE ACETYLATED LYSINES IN HISTONES AND MASTER TRANSCRIPTION FACTORS TO RECRUIT REGULATORY COMPLEX AND, FINALLY, MODIFY THE TRANSCRIPTIONAL PROGRAM. RECENT STUDIES INDICATE THAT BET PROTEINS ARE ESSENTIAL IN THE NF-KB-MEDIATED INFLAMMATORY RESPONSE, DURING THE ACTIVATION AND DIFFERENTIATION OF TH17-IMMUNE CELLS, AND IN PROFIBROTIC PROCESSES. HERE, WE REVIEW THIS NEW BODY OF DATA AND HIGHLIGHT THE EFFICIENCY OF BET INHIBITORS IN SEVERAL MODELS OF DISEASES. THE PROMISING RESULTS OBTAINED FROM THESE PRECLINICAL MODELS INDICATE THAT IT MAY BE TIME TO TRANSLATE THESE OUTCOMES TO THE TRANSPLANTATION FIELD, WHERE EPIGENETICS WILL BE OF INCREASING VALUE IN THE COMING YEARS. 2017 2 1688 31 DUAL BET/HDAC INHIBITION TO RELIEVE NEUROPATHIC PAIN: RECENT ADVANCES, PERSPECTIVES, AND FUTURE OPPORTUNITIES. DESPITE THE INTENSE RESEARCH ON DEVELOPING NEW THERAPIES FOR NEUROPATHIC PAIN STATES, AVAILABLE TREATMENTS HAVE LIMITED EFFICACY AND UNFAVORABLE SAFETY PROFILES. EPIGENETIC ALTERATIONS HAVE A GREAT INFLUENCE ON THE DEVELOPMENT OF CANCER AND NEUROLOGICAL DISEASES, AS WELL AS NEUROPATHIC PAIN. HISTONE ACETYLATION HAS PREVAILED AS ONE OF THE WELL INVESTIGATED EPIGENETIC MODIFICATIONS IN THESE DISEASES. ALTERED SPINAL ACTIVITY OF HISTONE DEACETYLASE (HDAC) AND BROMO AND EXTRA TERMINAL DOMAIN (BET) HAVE BEEN DESCRIBED IN NEUROPATHIC PAIN MODELS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS SHOWED PAIN-RELIEVING ACTIVITY. OVER THE LAST DECADES HDACS AND BETS HAVE BEEN THE FOCUS OF DRUG DISCOVERY STUDIES, LEADING TO THE DEVELOPMENT OF NUMEROUS SMALL-MOLECULE INHIBITORS. CLINICAL TRIALS TO EVALUATE THEIR ANTICANCER ACTIVITY SHOWED GOOD EFFICACY BUT RAISED TOXICITY CONCERNS THAT LIMITED TRANSLATION TO THE CLINIC. TO MAXIMIZE ACTIVITY AND MINIMIZE TOXICITY, THESE COMPOUNDS CAN BE APPLIED IN COMBINATION OF SUB-MAXIMAL DOSES TO PRODUCE ADDITIVE OR SYNERGISTIC INTERACTIONS (COMBINATION THERAPY). RECENTLY, OF PARTICULAR INTEREST, DUAL BET/HDAC INHIBITORS (MULTI-TARGET DRUGS) HAVE BEEN DEVELOPED TO ASSURE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE. THIS REVIEW WILL SUMMARIZE THE MOST RECENT ADVANCES WITH THESE STRATEGIES, DESCRIBING ADVANTAGES AND LIMITATIONS OF SINGLE DRUG TREATMENT VS COMBINATION REGIMENS. THIS REVIEW WILL ALSO PROVIDE A FOCUS ON DUAL BET/HDAC DRUG DISCOVERY INVESTIGATIONS AS FUTURE THERAPEUTIC OPPORTUNITY FOR HUMAN THERAPY OF NEUROPATHIC PAIN. 2021 3 697 49 BROMODOMAIN AND EXTRATERMINAL PROTEINS AS NOVEL EPIGENETIC TARGETS FOR RENAL DISEASES. EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION AND HISTONE MODIFICATIONS, ARE DYNAMIC PROCESSES THAT REGULATE THE GENE EXPRESSION TRANSCRIPTIONAL PROGRAM IN NORMAL AND DISEASED STATES. THE BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN FAMILY (BRD2, BRD3, BRD4, AND BRDT) ARE EPIGENETIC READERS THAT, VIA BROMODOMAINS, REGULATE GENE TRANSCRIPTION BY BINDING TO ACETYLATED LYSINE RESIDUES ON HISTONES AND MASTER TRANSCRIPTIONAL FACTORS. EXPERIMENTAL DATA HAVE DEMONSTRATED THE INVOLVEMENT OF SOME BET PROTEINS IN MANY PATHOLOGICAL CONDITIONS, INCLUDING TUMOR DEVELOPMENT, INFECTIONS, AUTOIMMUNITY, AND INFLAMMATION. SELECTIVE BROMODOMAIN INHIBITORS ARE EPIGENETIC DRUGS THAT BLOCK THE INTERACTION BETWEEN BET PROTEINS AND ACETYLATED PROTEINS, THUS EXERTING BENEFICIAL EFFECTS. RECENT DATA HAVE DESCRIBED THE BENEFICIAL EFFECT OF BET INHIBITION ON EXPERIMENTAL RENAL DISEASES. EMERGING EVIDENCE UNDERSCORES THE IMPORTANCE OF ENVIRONMENTAL MODIFICATIONS IN THE ORIGIN OF PATHOLOGICAL FEATURES IN CHRONIC KIDNEY DISEASES (CKD). SEVERAL CELLULAR PROCESSES SUCH AS OXIDATION, METABOLIC DISORDERS, CYTOKINES, INFLAMMATION, OR ACCUMULATED UREMIC TOXINS MAY INDUCE EPIGENETIC MODIFICATIONS THAT REGULATE KEY PROCESSES INVOLVED IN RENAL DAMAGE AND IN OTHER PATHOLOGICAL CONDITIONS OBSERVED IN CKD PATIENTS. HERE, WE REVIEW HOW TARGETING BROMODOMAINS IN BET PROTEINS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL DISEASES AND IN ASSOCIATED COMPLICATIONS FOUND IN CKD PATIENTS, SUCH AS CARDIOVASCULAR DAMAGE, HIGHLIGHTING THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES AGAINST BET PROTEINS FOR CKD TREATMENT AND ASSOCIATED RISKS. 2019 4 700 35 BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4): A KEY PLAYER IN INFLAMMATORY BOWEL DISEASE AND POTENTIAL TO INSPIRE EPIGENETIC THERAPEUTICS. INTRODUCTION: INFLAMMATORY BOWEL DISEASES (IBDS) ARE DEBILITATING CHRONIC INFLAMMATORY DISORDERS WITH INCREASING PREVALENCE WORLDWIDE. EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS CRITICAL IN CONTROLLING GENE EXPRESSION OF IBD-ASSOCIATED INFLAMMATORY CYTOKINE NETWORKS. BRD4 AS A PROMISING THERAPEUTIC TARGET IS ALSO TIGHTLY ASSOCIATED WITH MANY OTHER DISEASES, SUCH AS AIRWAY INFLAMMATION AND FIBROSIS, CANCERS, INFECTIOUS DISEASES AND CENTRAL NERVOUS SYSTEM DISORDERS. AREAS COVERED: THIS REVIEW BRIEFLY SUMMARIZED THE CRITICAL ROLE OF BRD4 IN THE PATHOGENESIS OF IBDS AND THE CURRENT CLINICAL LANDSCAPE OF DEVELOPING BROMODOMAIN AND EXTRA TERMINAL DOMAIN (BET) INHIBITORS. THE CHALLENGES AND OPPORTUNITIES AS WELL AS FUTURE DIRECTIONS OF TARGETING BRD4 INHIBITION FOR POTENTIAL IBD MEDICATIONS WERE ALSO DISCUSSED. EXPERT OPINION: TARGETING BRD4 WITH POTENT AND SPECIFIC INHIBITORS MAY OFFER NOVEL EFFECTIVE THERAPEUTICS FOR IBD PATIENTS, PARTICULARLY THOSE WHO ARE REFRACTORY TO ANTI-TNFALPHA THERAPY AND IBD-RELATED PROFIBROTIC. DEVELOPING HIGHLY SPECIFIC BRD4 INHIBITORS FOR IBD MEDICATIONS MAY HELP ERASE THE DRAWBACKS OF MOST CURRENT PAN-BET/BRD4 INHIBITORS, SUCH AS OFF-TARGET EFFECTS, POOR ORAL BIOAVAILABILITY, AND LOW GUT MUCOSAL ABSORBANCE. NOVEL STRATEGIES SUCH AS COMBINATORIAL THERAPY, BRD4-BASED DUAL INHIBITORS AND PROTEOLYSIS TARGETING CHIMERAS (PROTACS) MAY ALSO HAVE GREAT POTENTIAL TO MITIGATE SIDE EFFECTS AND OVERCOME DRUG RESISTANCE DURING IBD TREATMENT. 2023 5 689 47 BRD4 AS A THERAPEUTIC TARGET IN PULMONARY DISEASES. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC MODULATORS THAT REGULATE GENE TRANSCRIPTION THROUGH INTERACTING WITH ACETYLATED LYSINE RESIDUES OF HISTONE PROTEINS. BET PROTEINS HAVE MULTIPLE ROLES IN REGULATING KEY CELLULAR FUNCTIONS SUCH AS CELL PROLIFERATION, DIFFERENTIATION, INFLAMMATION, OXIDATIVE AND REDOX BALANCE, AND IMMUNE RESPONSES. AS A RESULT, BET PROTEINS HAVE BEEN FOUND TO BE ACTIVELY INVOLVED IN A BROAD RANGE OF HUMAN LUNG DISEASES INCLUDING ACUTE LUNG INFLAMMATION, ASTHMA, PULMONARY ARTERIAL HYPERTENSION, PULMONARY FIBROSIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). DUE TO THE IDENTIFICATION OF SPECIFIC SMALL MOLECULAR INHIBITORS OF BET PROTEINS, TARGETING BET IN THESE LUNG DISEASES HAS BECOME AN AREA OF INCREASING INTEREST. EMERGING EVIDENCE HAS DEMONSTRATED THE BENEFICIAL EFFECTS OF BET INHIBITORS IN PRECLINICAL MODELS OF VARIOUS HUMAN LUNG DISEASES. THIS IS, IN GENERAL, LARGELY RELATED TO THE ABILITY OF BET PROTEINS TO BIND TO PROMOTERS OF GENES THAT ARE CRITICAL FOR INFLAMMATION, DIFFERENTIATION, AND BEYOND. BY MODULATING THESE CRITICAL GENES, BET PROTEINS ARE INTEGRATED INTO THE PATHOGENESIS OF DISEASE PROGRESSION. THE INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY OF BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS OF PARTICULAR INTEREST, SEEMS TO ACT INDEPENDENTLY OF ITS BROMODOMAIN BINDING ACTIVITY, AND HAS IMPLICATION IN SOME CONTEXTS. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF THE RESEARCH ON BET PROTEINS WITH A FOCUS ON BRD4 IN SEVERAL MAJOR HUMAN LUNG DISEASES, THE UNDERLYING MOLECULAR MECHANISMS, AS WELL AS FINDINGS OF TARGETING BET PROTEINS USING PHARMACEUTICAL INHIBITORS IN DIFFERENT LUNG DISEASES PRECLINICALLY. 2023 6 1650 34 DOMAIN-SELECTIVE TARGETING OF BET PROTEINS IN CANCER AND IMMUNOLOGICAL DISEASES. CANCER AND INFLAMMATION ARE STRONGLY INTERCONNECTED PROCESSES. CHRONIC INFLAMMATORY PATHOLOGIES CAN BE AT THE HEART OF TUMOR DEVELOPMENT; SIMILARLY, TUMOR-ELICITED INFLAMMATION IS A CONSEQUENCE OF MANY CANCERS. THE MECHANISTIC INTERDEPENDENCE BETWEEN CANCER AND INFLAMMATORY PATHOLOGIES POINTS TOWARD COMMON PROTEIN EFFECTORS WHICH REPRESENT POTENTIAL SHARED TARGETS FOR PHARMACOLOGICAL INTERVENTION. EPIGENETIC MECHANISMS OFTEN DRIVE RESISTANCE TO CANCER THERAPY AND IMMUNOMODULATORY STRATEGIES. THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC ADAPTERS WHICH PLAY A MAJOR ROLE IN CONTROLLING CELL PROLIFERATION AND THE PRODUCTION OF INFLAMMATORY MEDIATORS. A PLETHORA OF SMALL MOLECULES AIMED AT INHIBITING BET PROTEIN FUNCTION TO TREAT CANCER AND INFLAMMATORY DISEASES HAVE POPULATED ACADEMIC AND INDUSTRY EFFORTS IN THE LAST 10 YEARS. IN THIS REVIEW, WE WILL DISCUSS RECENT PHARMACOLOGICAL APPROACHES AIMED AT TARGETING A SINGLE OR A SUBSET OF THE EIGHT BROMODOMAINS WITHIN THE BET FAMILY WHICH HAVE THE POTENTIAL TO TEASE APART CLINICAL EFFICACY AND SAFETY SIGNALS OF BET INHIBITORS. 2020 7 4582 36 N-TERMINAL BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-P65 INTERACTION AND REDUCE INDUCIBLE NITRIC OXIDE SYNTHASE TRANSCRIPTION IN PANCREATIC BETA-CELLS. CHRONIC INFLAMMATION OF PANCREATIC ISLETS IS A KEY DRIVER OF BETA-CELL DAMAGE THAT CAN LEAD TO AUTOREACTIVITY AND THE EVENTUAL ONSET OF AUTOIMMUNE DIABETES (T1D). IN THE ISLET, ELEVATED LEVELS OF PROINFLAMMATORY CYTOKINES INDUCE THE TRANSCRIPTION OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) GENE, NOS2, ULTIMATELY RESULTING IN INCREASED NITRIC OXIDE (NO). EXCESSIVE OR PROLONGED EXPOSURE TO NO CAUSES BETA-CELL DYSFUNCTION AND FAILURE ASSOCIATED WITH DEFECTS IN MITOCHONDRIAL RESPIRATION. RECENT STUDIES SHOWED THAT INHIBITION OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY OF PROTEINS, A DRUGGABLE CLASS OF EPIGENETIC READER PROTEINS, PREVENTS THE ONSET AND PROGRESSION OF T1D IN THE NON-OBESE DIABETIC MOUSE MODEL. WE HYPOTHESIZED THAT BET PROTEINS CO-ACTIVATE TRANSCRIPTION OF CYTOKINE-INDUCED INFLAMMATORY GENE TARGETS IN BETA-CELLS AND THAT SELECTIVE, CHEMOTHERAPEUTIC INHIBITION OF BET BROMODOMAINS COULD REDUCE SUCH TRANSCRIPTION. HERE, WE INVESTIGATED THE ABILITY OF BET BROMODOMAIN SMALL MOLECULE INHIBITORS TO REDUCE THE BETA-CELL RESPONSE TO THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 1 BETA (IL-1BETA). BET BROMODOMAIN INHIBITION ATTENUATED IL-1BETA-INDUCED TRANSCRIPTION OF THE INFLAMMATORY MEDIATOR NOS2 AND CONSEQUENT INOS PROTEIN AND NO PRODUCTION. REDUCED NOS2 TRANSCRIPTION IS CONSISTENT WITH INHIBITION OF NF-KAPPAB FACILITATED BY DISRUPTING THE INTERACTION OF A SINGLE BET FAMILY MEMBER, BRD4, WITH THE NF-KAPPAB SUBUNIT, P65. USING RECENTLY REPORTED SELECTIVE INHIBITORS OF THE FIRST AND SECOND BET BROMODOMAINS, INHIBITION OF ONLY THE FIRST BROMODOMAIN WAS NECESSARY TO REDUCE THE INTERACTION OF BRD4 WITH P65 IN BETA-CELLS. MOREOVER, INHIBITION OF THE FIRST BROMODOMAIN WAS SUFFICIENT TO MITIGATE IL-1BETA-DRIVEN DECREASES IN MITOCHONDRIAL OXYGEN CONSUMPTION RATES AND BETA-CELL VIABILITY. BY IDENTIFYING A ROLE FOR THE INTERACTION BETWEEN BRD4 AND P65 IN CONTROLLING THE RESPONSE OF BETA-CELLS TO PROINFLAMMATORY CYTOKINES, WE PROVIDE MECHANISTIC INFORMATION ON HOW BET BROMODOMAIN INHIBITION CAN DECREASE INFLAMMATION. THESE STUDIES ALSO SUPPORT THE POTENTIAL THERAPEUTIC APPLICATION OF MORE SELECTIVE BET BROMODOMAIN INHIBITORS IN ATTENUATING BETA-CELL INFLAMMATION. 2022 8 757 34 CARTILAGE REPAIR BY MESENCHYMAL STEM CELLS: CLINICAL TRIAL UPDATE AND PERSPECTIVES. OSTEOARTHRITIS IS A DEGENERATIVE DISEASE OF JOINTS WITH DESTRUCTION OF ARTICULAR CARTILAGE ASSOCIATED WITH SUBCHONDRAL BONE HYPERTROPHY AND INFLAMMATION. OA IS THE LEADING CAUSE OF JOINT PAIN RESULTING IN SIGNIFICANT WORSENING OF THE QUALITY-OF-LIFE IN THE ELDERLY. NUMEROUS EFFORTS HAVE BEEN SPENT TO OVERCOME THE INHERENTLY POOR HEALING ABILITY OF ARTICULAR CARTILAGE. MESENCHYMAL STEM CELLS (MSCS) HAVE BEEN IN THE LIMELIGHT OF CELL-BASED THERAPIES TO PROMOTE CARTILAGE REPAIR. DESPITE PROGRESSIVE ADVANCEMENTS IN MSC MANIPULATION AND THE INTRODUCTION OF VARIOUS BIOACTIVE SCAFFOLDS AND GROWTH FACTORS IN PRECLINICAL STUDIES, CURRENT CLINICAL TRIALS ARE STILL AT EARLY STAGES WITH PRELIMINARY AIMS TO EVALUATE SAFETY, FEASIBILITY AND EFFICACY. THIS REVIEW SUMMARISES RECENTLY REPORTED MSC-BASED CLINICAL TRIALS AND DISCUSSES NEW RESEARCH DIRECTIONS WITH PARTICULAR FOCUS ON THE POTENTIAL APPLICATION OF MSC-DERIVED EXTRACELLULAR VEHICLES, MIRNAS AND ADVANCED GENE EDITING TECHNIQUES WHICH MAY SHED LIGHT ON THE DEVELOPMENT OF NOVEL TREATMENT STRATEGIES. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: THIS REVIEW SUMMARISES RECENT MSC-RELATED CLINICAL RESEARCH THAT FOCUSES ON CARTILAGE REPAIR. WE ALSO PROPOSE A NOVEL POSSIBLE TRANSLATIONAL DIRECTION FOR HYALINE CARTILAGE FORMATION AND A NEW PARADIGM MAKING USE OF EXTRA-CELLULAR SIGNALLING AND EPIGENETIC REGULATION IN THE APPLICATION OF MSCS FOR CARTILAGE REPAIR. 2017 9 591 35 BET BROMODOMAIN PROTEINS AND EPIGENETIC REGULATION OF INFLAMMATION: IMPLICATIONS FOR TYPE 2 DIABETES AND BREAST CANCER. CHRONIC INFLAMMATION DRIVES PATHOLOGIES ASSOCIATED WITH TYPE 2 DIABETES (T2D) AND BREAST CANCER. OBESITY-DRIVEN INFLAMMATION MAY EXPLAIN INCREASED RISK AND MORTALITY OF BREAST CANCER WITH T2D REPORTED IN THE EPIDEMIOLOGY LITERATURE. THERAPEUTIC APPROACHES TO TARGET INFLAMMATION IN BOTH T2D AND CANCER HAVE SO FAR FALLEN SHORT OF THE EXPECTED IMPROVEMENTS IN DISEASE PATHOGENESIS OR OUTCOMES. THE TARGETING OF EPIGENETIC REGULATORS OF CYTOKINE TRANSCRIPTION AND CYTOKINE SIGNALING OFFERS ONE PROMISING, UNTAPPED APPROACH TO TREATING DISEASES DRIVEN BY INFLAMMATION. RECENT WORK HAS DEEPLY IMPLICATED THE BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS, WHICH ARE ACETYLATED HISTONE "READERS", IN EPIGENETIC REGULATION OF INFLAMMATION. THIS REVIEW FOCUSES ON INFLAMMATION ASSOCIATED WITH T2D AND BREAST CANCER, AND THE POSSIBILITY OF TARGETING BET PROTEINS AS AN APPROACH TO REGULATING INFLAMMATION IN THE CLINIC. UNDERSTANDING INFLAMMATION IN THE CONTEXT OF BET PROTEIN REGULATION MAY PROVIDE A BASIS FOR DESIGNING PROMISING THERAPEUTICS FOR T2D AND BREAST CANCER. 2017 10 595 40 BET PROTEINS REGULATE EXPRESSION OF OSR1 IN EARLY KIDNEY DEVELOPMENT. IN UTERO RENAL DEVELOPMENT IS SUBJECT TO MATERNAL METABOLIC AND ENVIRONMENTAL INFLUENCES AFFECTING LONG-TERM RENAL FUNCTION AND THE RISK OF DEVELOPING CHRONIC KIDNEY FAILURE AND CARDIOVASCULAR DISEASE. EPIGENETIC PROCESSES HAVE BEEN IMPLICATED IN THE ORCHESTRATION OF RENAL DEVELOPMENT AND PRENATAL PROGRAMMING OF NEPHRON NUMBER. HOWEVER, THE ROLE OF MANY EPIGENETIC MODIFIERS FOR KIDNEY DEVELOPMENT IS STILL UNCLEAR. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ACT AS HISTONE ACETYLATION READER MOLECULES AND PROMOTE GENE TRANSCRIPTION. BET FAMILY MEMBERS BRD2, BRD3 AND BRD4 ARE EXPRESSED IN THE NEPHROGENIC ZONE DURING KIDNEY DEVELOPMENT. HERE, THE EFFECT OF THE BET INHIBITOR JQ1 ON RENAL DEVELOPMENT IS EVALUATED. INHIBITION OF BET PROTEINS VIA JQ1 LEADS TO REDUCED GROWTH OF METANEPHRIC KIDNEY CULTURES, LOSS OF THE NEPHRON PROGENITOR CELL POPULATION, AND PREMATURE AND DISTURBED NEPHRON DIFFERENTIATION. GENE EXPRESSION OF KEY NEPHRON PROGENITOR TRANSCRIPTION FACTOR OSR1 IS DOWNREGULATED AFTER 24 H BET INHIBITION, WHILE LHX1 AND PAX8 EXPRESSION IS INCREASED. MINING OF BRD4 CHIP-SEQ AND GENE EXPRESSION DATA IDENTIFY OSR1 AS A KEY FACTOR REGULATED BY BRD4-CONTROLLED GENE ACTIVATION. INHIBITION OF BRD4 BY BET INHIBITOR JQ1 LEADS TO DOWNREGULATION OF OSR1, THEREBY CAUSING A DISTURBANCE IN THE BALANCE OF NEPHRON PROGENITOR CELL SELF-RENEWAL AND PREMATURE DIFFERENTIATION OF THE NEPHRON, WHICH ULTIMATELY LEADS TO KIDNEY HYPOPLASIA AND DISTURBED NEPHRON DEVELOPMENT. THIS RAISES QUESTIONS ABOUT THE POTENTIAL TERATOGENIC EFFECTS OF BET INHIBITORS FOR EMBRYONIC DEVELOPMENT. IN SUMMARY, OUR WORK HIGHLIGHTS THE ROLE OF BET PROTEINS FOR PRENATAL PROGRAMMING OF NEPHROGENESIS AND IDENTIFIES OSR1 AS A POTENTIAL TARGET OF BET PROTEINS. 2021 11 592 35 BET BROMODOMAIN PROTEINS REGULATE TRANSCRIPTIONAL REPROGRAMMING IN GENETIC DILATED CARDIOMYOPATHY. THE BROMODOMAIN AND EXTRATERMINAL (BET) FAMILY COMPRISES EPIGENETIC READER PROTEINS THAT ARE IMPORTANT REGULATORS OF INFLAMMATORY AND HYPERTROPHIC GENE EXPRESSION IN THE HEART. WE PREVIOUSLY IDENTIFIED THE ACTIVATION OF PROINFLAMMATORY GENE NETWORKS AS A KEY EARLY DRIVER OF DILATED CARDIOMYOPATHY (DCM) IN TRANSGENIC MICE EXPRESSING A MUTANT FORM OF PHOSPHOLAMBAN (PLNR9C) - A GENETIC CAUSE OF DCM IN HUMANS. WE HYPOTHESIZED THAT BETS COACTIVATE THIS INFLAMMATORY PROCESS, REPRESENTING A CRITICAL NODE IN THE PROGRESSION OF DCM. TO TEST THIS HYPOTHESIS, WE TREATED PLNR9C OR AGE-MATCHED WT MICE LONGITUDINALLY WITH THE SMALL MOLECULE BET BROMODOMAIN INHIBITOR JQ1 OR VEHICLE. BET INHIBITION ABROGATED ADVERSE CARDIAC REMODELING, REDUCED CARDIAC FIBROSIS, AND PROLONGED SURVIVAL IN PLNR9C MICE BY INHIBITING EXPRESSION OF PROINFLAMMATORY GENE NETWORKS AT ALL STAGES OF DISEASE. SPECIFICALLY, JQ1 HAD PROFOUND EFFECTS ON PROINFLAMMATORY GENE NETWORK EXPRESSION IN CARDIAC FIBROBLASTS, WHILE HAVING LITTLE EFFECT ON GENE EXPRESSION IN CARDIOMYOCYTES. CARDIAC FIBROBLAST PROLIFERATION WAS ALSO SUBSTANTIALLY REDUCED BY JQ1. MECHANISTICALLY, WE DEMONSTRATED THAT BRD4 SERVES AS A DIRECT AND ESSENTIAL REGULATOR OF NF-KAPPAB-MEDIATED PROINFLAMMATORY GENE EXPRESSION IN CARDIAC FIBROBLASTS. SUPPRESSING PROINFLAMMATORY GENE EXPRESSION VIA BET BROMODOMAIN INHIBITION COULD BE A NOVEL THERAPEUTIC STRATEGY FOR CHRONIC DCM IN HUMANS. 2020 12 5147 38 POTENTIAL ROLES OF LONG NONCODING RNAS AS THERAPEUTIC TARGETS IN ORGAN TRANSPLANTATION. ORGAN TRANSPLANTATION IS THE MOST PREFERRED TREATMENT OPTION FOR END-STAGE ORGAN DISEASES; HOWEVER, ALLOGRAFT REJECTION IS THE MAJOR HURDLE IN SUCCESSFUL LONG-TERM TRANSPLANT SURVIVAL. IN SPITE OF DEVELOPING BETTER HLA MATCHING AND MORE EFFECTIVE IMMUNOSUPPRESSIVE REGIMEN, ONE-YEAR GRAFT SURVIVAL HAS BEEN INCREASED BY NEARLY 90% AND THE INCIDENCE OF ACUTE REJECTION BY ONE-YEAR POST-TRANSPLANTATION HAS BEEN DECREASED BY 12.2% IN THE LAST DECADES, CHRONIC ALLOGRAFT REJECTION HAS REMAINED AS ONE OF THE MAJOR OBSTACLES TO THE LONG-LASTING SURVIVAL OF THE TRANSPLANTED ALLOGRAFT. THEREFORE, SEEMINGLY PREVENTING THE ALLOGRAFT REJECTION AND INDUCING IMMUNOLOGICAL TOLERANCE AGAINST TRANSPLANTED ALLOGRAFTS IS ONE OF THE PRIMARY GOALS IN TRANSPLANTATION RESEARCH TO ENABLE LONG-LASTING GRAFT SURVIVAL. VARIOUS MECHANISMS SUCH AS LONG NONCODING RNAS (LNCRNAS) HAVE BEEN PROPOSED THAT INDUCE IMMUNE TOLERANCE BY MODULATING THE GENE EXPRESSION AND REGULATING INNATE AND ADAPTIVE IMMUNE RESPONSES DURING TRANSPLANTATION. BESIDES, BECAUSE OF INVOLVEMENT IN REGULATING EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSLATIONAL MECHANISMS, LNCRNAS COULD AFFECT ALLOGRAFT STATUS. THEREFORE, THESE MOLECULES COULD BE CONSIDERED AS THE POTENTIAL TARGETS FOR PREDICTION, PROGNOSIS, DIAGNOSIS, AND TREATMENT OF GRAFT REJECTION. IT IS SUGGESTED THAT THE NONINVASIVE PREDICTIVE BIOMARKERS HOLD PROMISE TO OVERCOME THE CURRENT LIMITATIONS OF CONVENTIONAL TISSUE BIOPSY IN THE DIAGNOSIS OF REJECTION. HENCE, THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF LNCRNAS AND THEIR FUNCTION TO FACILITATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RISK OF GRAFT REJECTION, AND THE SUGGESTIVE THERAPEUTIC CHOICES AFTER TRANSPLANTATION. 2022 13 3744 40 INSIGHTS INTO THE CRYSTAL STRUCTURE OF BRD2-BD2 - PHENANTHRIDINONE COMPLEX AND THEORETICAL STUDIES ON PHENANTHRIDINONE ANALOGS. BROMODOMAIN AND EXTRA-TERMINAL FAMILY PROTEINS RECOGNIZE THE ACETYLATED HISTONE CODE ON CHROMATIN AND PARTICIPATE IN DOWNSTREAM PROCESSES LIKE DNA REPLICATION, MODIFICATION, AND REPAIR. AS PART OF EPIGENETIC APPROACHES, BRD2 AND BRD4 WERE IDENTIFIED AS PUTATIVE TARGETS, FOR THE MANAGEMENT OF CHRONIC DISEASES. WE HAVE RECENTLY REPORTED THE DISCOVERY OF A NEW SCAFFOLD OF THE PHENANTHRIDINONE-BASED INHIBITOR (L10) OF THE SECOND BROMODOMAIN OF BRD2 (BRD2-BD2). HERE, WE PRESENT THE CRYSTAL STRUCTURE OF THE BRD2-BD2, REFINED TO 1.4 A RESOLUTION, IN COMPLEX WITH BETA-MERCAPTOETHANOL (A COMPONENT OF THE PROTEIN BUFFER). THE BETA-MERCAPTOETHANOL COVALENTLY LINKS TO C425 OF BD2 IN THE ACETYL-LYSINE BINDING POCKET, TO FORM A MODIFIED CYSTEINE MERCAPTOETHANOL (CME). THE CME MODIFICATION SIGNIFICANTLY HINDERS THE ENTRY OF LIGANDS INTO THE BD2 BINDING POCKET, SUGGESTING THAT BETA-MERCAPTOETHANOL SHOULD BE REMOVED DURING PROTEIN PRODUCTION PROCESS. NEXT, TO CONFIRM WHETHER PHENANTHRIDIONONE SCAFFOLD IS A NEW INHIBITOR FAMILY OF BRD2-BD2, WE HAVE DETERMINED THE CRYSTAL STRUCTURE OF BD2 IN COMPLEX WITH 6(5H)-PHENANTHRIDINONE (A CORE MOIETY OF L10), REFINED TO 1.28 A RESOLUTION. IT CONFIRMED THAT THE PHENANTHRIDINONE MOLECULE, UNAMBIGUOUSLY, BINDS TO BD2. MOREOVER, WE PERFORMED MOLECULAR DOCKING AND MOLECULAR DYNAMIC STUDIES ON SELECTED PHENANTHRIDINONE ANALOGS. THE PREDICTED L10 ANALOGS ARE STABLE WITH ESSENTIAL HYDROPHOBIC AND HYDROPHILIC INTERACTIONS WITH BD2 DURING MOLECULAR DYNAMIC SIMULATIONS. WE PROPOSE THAT THE PREDICTED PHENANTHRIDINONE ANALOGS MAY BE POTENTIAL MOLECULES FOR INHIBITING THE BD2 FUNCTION OF ACETYLATED HISTONE RECOGNITION. 2018 14 3333 32 HISTONE DEACETYLASE INHIBITORS AND DIABETIC KIDNEY DISEASE. DESPITE RECENT CLINICAL TRIAL ADVANCES AND IMPROVEMENTS IN CLINICAL CARE, KIDNEY DISEASE DUE TO DIABETES REMAINS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE WORLDWIDE. IN THE SEARCH FOR NEW TREATMENTS, RECENT ATTENTIONS HAVE TURNED TO DRUG REPURPOSING OPPORTUNITIES, INCLUDING STUDY OF THE HISTONE DEACETYLASE (HDAC) INHIBITOR CLASS OF AGENTS. HDACS ARE A GROUP OF ENZYMES THAT REMOVE FUNCTIONAL ACETYL GROUPS FROM HISTONE AND NON-HISTONE PROTEINS AND THEY CAN AFFECT CELLULAR FUNCTION THROUGH BOTH EPIGENETIC AND NON-EPIGENETIC MEANS. OVER THE PAST DECADE, SEVERAL HDAC INHIBITORS HAVE BEEN ADOPTED INTO CLINICAL PRACTICE, PRIMARILY FOR THE TREATMENT OF HEMATOLOGICAL MALIGNANCY, WHEREAS OTHER EXISTING THERAPIES (FOR INSTANCE VALPROATE) HAVE BEEN FOUND TO HAVE HDAC INHIBITORY EFFECTS. HERE WE REVIEW THE CURRENT HDAC INHIBITORS IN THE CLINIC AND UNDER DEVELOPMENT; THE LITERATURE EVIDENCE SUPPORTING THE RENOPROTECTIVE EFFECTS OF HDAC INHIBITORS IN EXPERIMENTAL DIABETIC KIDNEY DISEASE; AND THE ADVERSE EFFECT PROFILES THAT MAY PREVENT EXISTING THERAPIES FROM ENTERING THE CLINIC FOR THIS INDICATION. WHEREAS RECENT RESEARCH EFFORTS HAVE SHED LIGHT ON THE FUNDAMENTAL ACTIONS OF HDACS IN THE DIABETIC KIDNEY, WHETHER THESE EFFORTS WILL TRANSLATE INTO NOVEL THERAPIES FOR PATIENTS WILL REQUIRE MORE SPECIFIC AND BETTER-TOLERATED THERAPIES. 2018 15 6687 28 VALIDATION OF THE EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A THERAPEUTIC TARGET FOR TREATMENT OF AIRWAY REMODELING. STRUCTURAL REMODELING IS CENTRAL TO THE INITIATION AND PROGRESSION OF MANY CHRONIC LUNG DISEASES, REPRESENTING AN IMPORTANT UNMET NEED. WE EXAMINE THE EVIDENCE SUPPORTING BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AS A VALIDATED BIOLOGICAL TARGET FOR TREATMENT OF AIRWAY REMODELING. IN EPITHELIAL CELLS AND FIBROBLASTS, BRD4 SERVES AS A SCAFFOLD FOR CHROMATIN REMODELING COMPLEXES IN ACTIVE SUPER-ENHANCERS. IN RESPONSE TO INFLAMMATORY STIMULI, BRD4 IS REPOSITIONED TO INNATE AND MESENCHYMAL GENES ACTIVATING THEIR PRODUCTION. PROOF-OF-CONCEPT STUDIES SHOW PROMISING BENEFIT OF SELECTIVE BRD4 INHIBITORS IN DISRUPTING EPITHELIAL MESENCHYMAL TRANSITION AND MYOFIBROBLAST TRANSITION IN DIVERSE MODELS OF LUNG INJURY. RECENT IDENTIFICATION OF BIOMARKERS OF BRD4 PROVIDES A BASIS FOR FURTHER DRUG DEVELOPMENT FOR APPLICATION IN VIRAL-INDUCED AIRWAY INFLAMMATION, COPD AND INTERSTITIAL LUNG DISEASES. 2020 16 1105 39 COMBINED INHIBITION OF HISTONE DEACETYLASES AND BET FAMILY PROTEINS AS EPIGENETIC THERAPY FOR NERVE INJURY-INDUCED NEUROPATHIC PAIN. CURRENT TREATMENTS FOR NEUROPATHIC PAIN HAVE OFTEN MODERATE EFFICACY AND PRESENT UNWANTED EFFECTS SHOWING THE NEED TO DEVELOP EFFECTIVE THERAPIES. ACCUMULATING EVIDENCE SUGGESTS THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN CHRONIC PAIN AND THE ANALGESIC ACTIVITY OF HISTONE DEACETYLASES (HDACS) INHIBITORS IS DOCUMENTED. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT INTERACT WITH ACETYLATED LYSINE RESIDUES ON HISTONES, BUT LITTLE IS KNOWN ABOUT THEIR IMPLICATION IN NEUROPATHIC PAIN. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE EFFECT OF THE COMBINATION OF HDAC AND BET INHIBITORS IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE. INTRANASAL ADMINISTRATION OF I-BET762 (BET INHIBITOR) OR SAHA (HDAC INHIBITOR) ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY AND THIS ANTIALLODYNIC ACTIVITY WAS IMPROVED BY CO-ADMINISTRATION OF BOTH DRUGS. SPINAL CORD SECTIONS OF SNI MICE SHOWED AN INCREASED EXPRESSION OF HDAC1 AND BRD4 PROTEINS AND COMBINATION PRODUCED A STRONGER REDUCTION COMPARED TO EACH EPIGENETIC AGENT ALONE. SAHA AND I-BET762, ADMINISTERED ALONE OR IN COMBINATION, COUNTERACTED THE SNI-INDUCED MICROGLIA ACTIVATION BY INHIBITING THE EXPRESSION OF IBA1, CD11B, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), THE ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1) WITH COMPARABLE EFFICACY. CONVERSELY, THE EPIGENETIC INHIBITORS SHOWED A MODEST EFFECT ON SPINAL PROINFLAMMATORY CYTOKINES CONTENT THAT WAS SIGNIFICANTLY POTENTIATED BY THEIR COMBINATION. PRESENT RESULTS INDICATE A KEY ROLE OF ACETYLATED HISTONES AND THEIR RECRUITMENT BY BET PROTEINS ON MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION. TARGETING NEUROPATHIC PAIN WITH THE COMBINATION OF HDAC AND BET INHIBITORS MAY REPRESENT A PROMISING NEW THERAPEUTIC OPTION. 2021 17 593 35 BET PROTEIN INHIBITION REGULATES CYTOKINE PRODUCTION AND PROMOTES NEUROPROTECTION AFTER SPINAL CORD INJURY. BACKGROUND: SPINAL CORD INJURY (SCI) USUALLY CAUSES A DEVASTATING LIFELONG DISABILITY FOR PATIENTS. AFTER A TRAUMATIC LESION, DISRUPTION OF THE BLOOD-SPINAL CORD BARRIER INDUCES THE INFILTRATION OF MACROPHAGES INTO THE LESION SITE AND THE ACTIVATION OF RESIDENT GLIAL CELLS, WHICH RELEASE CYTOKINES AND CHEMOKINES. THESE EVENTS RESULT IN A PERSISTENT INFLAMMATION, WHICH HAS BOTH DETRIMENTAL AND BENEFICIAL EFFECTS, BUT EVENTUALLY LIMITS FUNCTIONAL RECOVERY AND CONTRIBUTES TO THE APPEARANCE OF NEUROPATHIC PAIN. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE THE EXPRESSION OF INFLAMMATORY GENES BY INTERACTING WITH ACETYLATED LYSINE RESIDUES. WHILE BET INHIBITORS ARE A PROMISING THERAPEUTIC STRATEGY FOR CANCER, LITTLE IS KNOWN ABOUT THEIR IMPLICATION AFTER SCI. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY ROLE OF BET INHIBITORS IN THIS PATHOLOGIC CONDITION. METHODS: WE EVALUATED THE EFFECTIVENESS OF THE BET INHIBITOR JQ1 TO MODIFY MACROPHAGE REACTIVITY IN VITRO AND TO MODULATE INFLAMMATION IN A SCI MICE MODEL. WE ANALYZED THE EFFECTS OF BET INHIBITION IN PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PRODUCTION IN VITRO AND IN VIVO. WE DETERMINED THE EFFECTIVENESS OF BET INHIBITION IN TISSUE SPARING, INFLAMMATION, NEURONAL PROTECTION, AND BEHAVIORAL OUTCOME AFTER SCI. RESULTS: WE HAVE FOUND THAT THE BET INHIBITOR JQ1 REDUCED THE LEVELS OF PRO-INFLAMMATORY MEDIATORS AND INCREASED THE EXPRESSION OF ANTI-INFLAMMATORY CYTOKINES. A PROLONGED TREATMENT WITH JQ1 ALSO DECREASED REACTIVITY OF MICROGLIA/MACROPHAGES, ENHANCED NEUROPROTECTION AND FUNCTIONAL RECOVERY, AND ACUTELY REDUCED NEUROPATHIC PAIN AFTER SCI. CONCLUSIONS: BET PROTEIN INHIBITION IS AN EFFECTIVE TREATMENT TO REGULATE CYTOKINE PRODUCTION AND PROMOTE NEUROPROTECTION AFTER SCI. THESE NOVEL RESULTS DEMONSTRATE FOR THE FIRST TIME THAT TARGETING BET PROTEINS IS AN ENCOURAGING APPROACH FOR SCI REPAIR AND A POTENTIAL STRATEGY TO TREAT OTHER INFLAMMATORY PATHOLOGIES. 2019 18 5365 25 RECENT ADVANCES IN HEPATITIS B TREATMENT. HEPATITIS B VIRUS INFECTION AFFECTS OVER 250 MILLION CHRONIC CARRIERS, CAUSING MORE THAN 800,000 DEATHS ANNUALLY, ALTHOUGH A SAFE AND EFFECTIVE VACCINE IS AVAILABLE. CURRENTLY USED ANTIVIRAL AGENTS, PEGYLATED INTERFERON AND NUCLEOS(T)IDE ANALOGUES, HAVE MAJOR DRAWBACKS AND FAIL TO COMPLETELY ERADICATE THE VIRUS FROM INFECTED CELLS. THUS, ACHIEVING A "FUNCTIONAL CURE" OF THE INFECTION REMAINS A REAL CHALLENGE. RECENT FINDINGS CONCERNING THE VIRAL REPLICATION CYCLE HAVE LED TO DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES INCLUDING VIRAL ENTRY INHIBITORS, EPIGENETIC CONTROL OF CCCDNA, IMMUNE MODULATORS, RNA INTERFERENCE TECHNIQUES, RIBONUCLEASE H INHIBITORS, AND CAPSID ASSEMBLY MODULATORS. PROMISING PRECLINICAL RESULTS HAVE BEEN OBTAINED, AND THE LEADING MOLECULES UNDER DEVELOPMENT HAVE ENTERED CLINICAL EVALUATION. THIS REVIEW SUMMARIZES THE KEY STEPS OF THE HBV LIFE CYCLE, EXAMINES THE CURRENTLY APPROVED ANTI-HBV DRUGS, AND ANALYZES NOVEL HBV TREATMENT REGIMENS. 2021 19 3197 33 HDAC INHIBITORS: TARGETS FOR TUMOR THERAPY, IMMUNE MODULATION AND LUNG DISEASES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT PLAY A KEY ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELING CHROMATIN. INHIBITION OF HDACS IS A PROSPECTIVE THERAPEUTIC APPROACH FOR REVERSING EPIGENETIC ALTERATION IN SEVERAL DISEASES. IN PRECLINICAL RESEARCH, NUMEROUS TYPES OF HDAC INHIBITORS WERE DISCOVERED TO EXHIBIT POWERFUL AND SELECTIVE ANTICANCER PROPERTIES. HOWEVER, SUCH RESEARCH HAS REVEALED THAT THE EFFECTS OF HDAC INHIBITORS MAY BE FAR BROADER AND MORE INTRICATE THAN PREVIOUSLY THOUGHT. THIS REVIEW WILL PROVIDE INSIGHT INTO THE HDAC INHIBITORS AND THEIR MECHANISM OF ACTION WITH SPECIAL EMPHASIS ON THE SIGNIFICANCE OF HDAC INHIBITORS IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER. NANOCARRIER-MEDIATED HDAC INHIBITOR DELIVERY AND NEW APPROACHES FOR TARGETING HDACS ARE ALSO DISCUSSED. 2022 20 6899 22 [THE DEVELOPMENT HISTORY AND FUTURE PERSPECTIVE OF MOLECULARLY TARGETED THERAPY]. THE ORIGIN OF MOLECULARLY TARGETED DRUGS DATES BACK TO 'MAGIC BULLET' THEORY PROPOSED BY PAUL EHRLICH. THE SUCCESS OF ABL TYROSINE KINASE INHIBITOR, IMATINIB FOR THE TREATMENT OF CHRONIC MYELOID LEUKEMIA REALIZED THAT SMALL MOLECULES INHIBITING ATP BINDING CAN BECOME SPECIFIC INHIBITORS FOR THE RELEVANT KINASES. SUBSEQUENTLY, A NUMBER OF KINASE INHIBITORS WHICH TARGETS VARIOUS SIGNAL TRANSDUCTION MOLECULES, ARE IN THE CLINICAL FIELD OR UNDER DEVELOPMENT. THE CLINICAL SUCCESS OF ANTIBODY THERAPEUTICS HAS BEEN ACHIEVED BY THE GENETIC ENGINEERING WHICH MAKES HUMAN-MOUSE CHIMERIC, HUMANIZED OR HUMAN ANTIBODY. TO AUGMENT THE THERAPEUTIC EFFECTS OF ANTIBODY, RADIOISOTOPE-CONJUGATE ANTIBODY AND ANTIBODY-DRUG CONJUGATE HAVE COME TO THE CLINICAL FIELD. IN THE NEAR FUTURE, WE HAVE TO DEVELOP THE COMBINATION THERAPY OF MOLECULARLY TARGETED DRUGS AND ALSO INHIBITORS FOR EPIGENETIC AND TRANSCRIPTIONAL REGULATORS. 2014