The
bromo and extra C-terminal domain (BET) family of bromodomains
are involved in binding epigenetic marks on histone proteins, more
specifically acetylated lysine residues. This paper describes the
discovery and structure–activity relationships (SAR) of potent
benzodiazepine inhibitors that disrupt the function of the BET family
of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent,
selective compound I-BET762 that is now under evaluation in a phase
I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma
and other cancers.
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
The hypothalamic peptide orexin-A and the orexin-1 receptor are localized in areas of the brain and spinal cord associated with nociceptive processing. In the present study, localization was confirmed in the spinal cord and demonstrated in the dorsal root ganglion for both orexin-A and the orexin-1 receptor. The link with nociception was extended when orexin-A was shown to be analgesic when given i.v. but not s.c. in mouse and rat models of nociception and hyperalgesia. The efficacy of orexin-A was similar to that of morphine in the 50 degrees C hotplate test and the carrageenan-induced thermal hyperalgesia test. However, involvement of the opiate system in these effects was ruled out as they were blocked by the orexin-1 receptor antagonist SB-334867 but not naloxone. Orexin-1 receptor antagonists had no effect in acute nociceptive tests but under particular inflammatory conditions were pro-hyperalgesic, suggesting a tonic inhibitory orexin drive in these circumstances. These data demonstrate that the orexinergic system has a potential role in the modulation of nociceptive transmission.
Key Points• I-BET151 and I- induce cell cycle arrest and apoptosis in myeloma cells associated with MYC downregulation and HEXIM1 upregulation.• Preclinical functional and pharmacologic profiling of I-BET762 supports its use in phase 1 clinical studies.The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYCdependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation. (Blood. 2014; 123(5):697-705)
Generation and deposition of the amyloid b (Ab) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and c-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Ab, is an attractive therapeutic approach for the treatment of Alzheimer's disease. We have designed a selective non-peptidic BACE-1 inhibitor, GSK188909, that potently inhibits b-cleavage of APP and reduces levels of secreted and intracellular Ab in SHSY5Y cells expressing APP. In addition, we demonstrate that this compound can effectively lower brain Ab in vivo. In APP transgenic mice, acute oral administration of GSK188909 in the presence of a p-glycoprotein inhibitor to markedly enhance the exposure of GSK188909 in the brain decreases b-cleavage of APP and results in a significant reduction in the level of Ab40 and Ab42 in the brain. Encouragingly, subchronic dosing of GSK188909 in the absence of a p-glycoprotein inhibitor also lowers brain Ab. This pivotal first report of central Ab lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease.
R. K. (2020). Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype. Journal of Medicinal Chemistry.
1. In vitro studies with the selective dopamine D3 receptor antagonist SB-277011 were conducted in liver microsomes and homogenates from rat, dog, cynomolgus monkey and human to correlate the rate of metabolism with the in vivo pharmacokinetics of the compound in rat, dog and cynomolgus monkey. 2. In the presence of NADPH, SB-277011 was relatively stable in the presence of liver microsomes from rat, dog, cynomolgus monkey and human with an intrinsic clearance (CLi) of < 2 ml min(-1) g(-1) liver for all species. In total liver homogenates, SB-277011 was metabolized at a similar rate in rat and dog (CLi < 2 ml min(-1) g(-1) liver) to that in liver microsomes but in cynomolgus monkey and human (CLi = 9.9 and 45 ml min(-1) g(-1) liver, respectively) the intrinsic clearance was approximately 6- and 35-fold higher, respectively, than that in liver microsomes. 3. In the absence of NADPH, SR-277011 was rapidly cleared in liver homogenates from cynomolgus monkey and human (CLi = 7.4 and 27 ml min(-1) g(-1) liver, respectively) demonstrating that a significant pathway of metabolism of this compound was via an NADPH-independent non-microsomal oxidative route. This pathway was sensitive to inhibition with isovanillin suggesting that the enzyme responsible was aldehyde oxidase. 4. The in vivo pharmacokinetics showed that the plasma clearance of SB-277011 was low in rat (20 ml min(-1) kg(-1)), moderate in dog (14 ml min(-1) kg(-1)) and high in cynomolgus monkey (58 ml min(-1)kg(-1)), which is consistent with the in vitro findings and demonstrated a greater capacity for the monkey to metabolize this compound. The oral bioavailability of SB-277011 in rat, dog and cynomolgus monkey was 35, 43 and 2%, respectively. Given the high clearance of this compound in cynomolgus monkey, the low oral bioavailability is probably as a result of high first-pass elimination, specifically by aldehyde oxidase, rather than poor absorption. 5. The high in vitro clearance of SB-277011 in human liver homogenates and the involvement of aldehyde oxidase in the metabolism of SB-277011 indicates that the bioavailability of the compound is likely to be low in human.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.