Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of ...small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.
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•Development of small-molecule MYC inhibitors (MYCi) that engage MYC in cells•MYCi disrupt MYC/MAX complexes, promote MYC T58 phosphorylation and MYC degradation•MYCi show favorable pharmacokinetics, in vivo efficacy and tolerability in mouse tumor models•MYCi treatment synergizes with anti-PD1 immunotherapy
Han et al. develop inhibitors that disrupt MYC/MAX heterodimerization, enhance MYC degradation, and impair MYC-driven gene expression. One compound exhibits potent anti-tumor efficacy in mice with good tolerability, increases tumor immune cell infiltration, and sensitizes tumors to anti-PD1 immunotherapy.
A convergent, catalytic asymmetric formal 4 + 2 annulation for the synthesis of dihydroquinolones has been developed. Carboxylic acids can be employed as precursors to NHC enolates through an in situ ...activation strategy. Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach.
Neurotrophins are important for neuronal health and function. Here, statins, inhibitors of HMG-CoA reductase and cholesterol lowering drugs, were found to stimulate expression of neurotrophins in ...brain cells independent of the mevalonate pathway. Time-resolved fluorescence resonance energy transfer (FRET) analyses, computer-derived simulation, site-directed mutagenesis, thermal shift assay, and de novo binding followed by electrospray ionization tandem mass spectrometry (ESI-MS) demonstrates that statins serve as ligands of PPARα and that Leu331 and Tyr 334 residues of PPARα are important for statin binding. Upon binding, statins upregulate neurotrophins via PPARα-mediated transcriptional activation of cAMP-response element binding protein (CREB). Accordingly, simvastatin increases CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus of Ppara null mice receiving full-length lentiviral PPARα, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARα. This study identifies statins as ligands of PPARα, describes neurotrophic function of statins via the PPARα-CREB pathway, and analyzes the importance of PPARα in the therapeutic success of simvastatin in an animal model of Alzheimer’s disease.
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•Upregulation of neurotrophins by statins independent of the mevalonate pathway•Statins bind with Leu331 and Tyr334 residues of the ligand-binding domain of PPARα•Statins produce neurotrophins via the PPARα-CREB pathway•Simvastatin increases CREB and improves memory in an animal model of AD via PPARα
Roy et al. show that the cholesterol-lowering drugs statins increase the expression of neurotrophins in the brain by binding to the ligand-binding domain of PPARα, independent of the mevalonate pathway. Simvastatin also increases neurotrophin expression and improves memory and learning in a mouse model of Alzheimer’s disease.
Many patients with coronavirus disease 2019 in intensive care units suffer from cytokine storm. Although anti-inflammatory therapies are available to treat the problem, very often, these treatments ...cause immunosuppression. Because angiotensin-converting enzyme 2 (ACE2) on host cells serves as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to delineate a SARS-CoV-2-specific anti-inflammatory molecule, we designed a hexapeptide corresponding to the spike S1-interacting domain of ACE2 receptor (SPIDAR) that inhibited the expression of proinflammatory molecules in human A549 lung cells induced by pseudotyped SARS-CoV-2, but not vesicular stomatitis virus. Accordingly, wild-type (wt), but not mutated (m), SPIDAR inhibited SARS-CoV-2 spike S1-induced activation of NF-κB and expression of IL-6 and IL-1β in human lung cells. However, wtSPIDAR remained unable to reduce activation of NF-κB and expression of proinflammatory molecules in lungs cells induced by TNF-α, HIV-1 Tat, and viral dsRNA mimic polyinosinic-polycytidylic acid, indicating the specificity of the effect. The wtSPIDAR, but not mutated SPIDAR, also hindered the association between ACE2 and spike S1 of SARS-CoV-2 and inhibited the entry of pseudotyped SARS-CoV-2, but not vesicular stomatitis virus, into human ACE2-expressing human embryonic kidney 293 cells. Moreover, intranasal treatment with wtSPIDAR, but not mutated SPIDAR, inhibited lung activation of NF-κB, protected lungs, reduced fever, improved heart function, and enhanced locomotor activities in SARS-CoV-2 spike S1-intoxicated mice. Therefore, selective targeting of SARS-CoV-2 spike S1-to-ACE2 interaction by wtSPIDAR may be beneficial for coronavirus disease 2019.
A
bstract
Weaving knots
W
(
p, n
) of type (
p, n
) denote an infinite family of hyperbolic knots which have not been addressed by the knot theorists as yet. Unlike the well known (
p, n
) torus ...knots, we do not have a closed-form expression for HOMFLY-PT and the colored HOMFLY-PT for
W
(
p, n
). In this paper, we confine to a hybrid generalization of
W
(3
, n
) which we denote as
W
̂
3
(
m, n
) and obtain closed form expression for HOMFLY-PT using the Reshitikhin and Turaev method involving
ℛ
-matrices. Further, we also compute
r
-colored HOMFLY-PT for
W
(3
, n
). Surprisingly, we observe that trace of the product of two dimensional
ℛ
̂
-matrices can be written in terms of infinite family of Laurent polynomials
V
n
,
t
q
whose absolute coefficients has interesting relation to the Fibonacci numbers
ℱ
n
. We also computed reformulated invariants and the BPS integers in the context of topological strings. From our analysis, we propose that certain refined BPS integers for weaving knot
W
(3
, n
) can be explicitly derived from the coefficients of Chebyshev polynomials of first kind.
Induction of TLR2 activation depends on its association with the adapter protein MyD88. We have found that TLR2 and MyD88 levels are elevated in the hippocampus and cortex of patients with ...Alzheimer's disease (AD) and in a 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from a therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. Interestingly, WT TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, dsRNA, bacterial lipopolysaccharide, flagellin, or CpG DNA. After intranasal administration, WT TIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, WT TIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to its effects in 5XFAD mice, WT TIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of the activated status of 1 component of the innate immune system by WT TIDM peptide may be beneficial in AD as well as other disorders in which TLR2/MyD88 signaling plays a role in disease pathogenesis.
The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity ...with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.
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•Discovery of small-molecule inhibitors of SEC and transcription elongation by Pol II•KL-1 and KL-2 disrupt the cyclin T1-AFF4 interaction within SEC•SEC inhibitors attenuate SEC-dependent rapid transcriptional responses•MYC transcriptional programs are inhibited by SEC chemical disruptors KL-1/KL-2
Targeting transcriptional elongation with small-molecule inhibitors of the super elongation complex blocks transcriptional programs driven by the oncogene MYC
The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling ...pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target.
Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our ...in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced α-ketoglutarate (αKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBMs to support macromolecular synthesis, aggressive growth, and therapy resistance.
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•Wild-type IDH1 is overexpressed in GBMs and other solid and systemic malignancies•IDH1 promotes tumor cell growth in vitro and in vivo and decreases GBM PDX survival•IDH1 regulates lipid biosynthesis, redox homeostasis, and differentiation•Pharmacological inhibition of IDH1 reduces GBM growth in vitro and in vivo
Calvert et al. demonstrate that wild-type IDH1 is overexpressed in glioblastoma and that genetic or pharmacological suppression of IDH1 activity reduces tumor cell growth through effect on lipid production, redox homeostasis, and the regulation of cellular differentiation.
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