Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7 − 12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Summary
LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 ...demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.
3-(Imidazo1,2-
apyridin-3-yl)-, its aza-analogs, and 3-(pyrazolo1,5-
apyridin-3-yl)-4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl))maleimides are very potent inhibitors of GSK3 (⩽5
nM) ...with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII.
Many 3-aryl-4-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100
nM IC
50), although few show significant selectivity (>100
×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo1,2-
apyridin-3-yl), 3-(pyrazolo1,5-
apyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5
nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
Abstract
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. While targeting upstream nodes with RAF and MEK ...inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. ERK inhibitors have the potential to address resistance caused by ERK reactivation. Herein, a potent, selective small molecule ERK1/2 inhibitor is described. LY3214996 possesses an optimal balance of potency (hERK1 IC50 5 nM, hERK2 IC50 5nM, pRSK IC50 0.43 µM), solubility (FaSSIF solubility at pH 6.5 0.133 µM), PK properties (dog, AUCoral 23800 nM*hr, CL 12.1 mL/min/kg, bioavailability 75.4%), IVTI (TED50 =16 mg/kg pRSK1) and demonstrated significant in vivo efficacy in several human cancer xenograft models. LY3214996 is currently undergoing early clinical evaluation.
Citation Format: Gaiying Zhao, William T. McMillen, Shufen Cai, Baohui Zhao, Matthew Whitesell, Wenjuan Wu, Karen Huss, Bryan Anderson, Xiu-Juan Yuan, Susan Jaken, Lisa Kindler, Robert S. Flack, Denis McCann, Brian Mathes, Andrew J. Dropsey, Jennie Walgren, Eunice Yuen, Jason Manro, Xueqian Gong, Guillermo Cortez, Johnathan McLean, Michael J. Rodriguez, Ramon V. Tiu, Shripad V. Bhagwat, Sajan Joseph. Identifying high quality, potent and selective pyrimidinylthienopyrrolone inhibitors of ERK1/2 kinase: LY3214996 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3231. doi:10.1158/1538-7445.AM2017-3231
Spermatogonial stem cells (SSCs) are a self-renewing population of adult stem cells capable of producing progeny cells for sperm production throughout the life of the male. Regulation of the SSC ...population includes establishment and maintenance of a niche microenvironment in the seminiferous tubules of the testis. Signaling from somatic cells within the niche determines the fate of SSCs by either supporting self-renewal or initiating differentiation leading to meiotic entry and production of spermatozoa. Despite the importance of these processes, little is known about the biochemical and cellular mechanisms that govern SSC fate and identity. This review discusses research findings regarding systemic, endocrine, and local cues that stimulate somatic niche cells to produce factors that contribute to the homeostasis of SSCs in mammals. In addition to their importance for male fertility, SSCs represent a model for the investigation of adult stem cells because they can be maintained in culture, and the presence, proliferation, or loss of SSCs in a cell population can be determined with the use of a transplantation assay. Defining the mechanisms that regulate the self-renewal and differentiation of SSCs will fundamentally improve the understanding of male fertility and provide information about the regulation of adult stem cells in other tissues.
Activating epidermal growth factor receptor gene mutations (EGFRm) are relatively common in non-small cell lung cancer (NSCLC) and are predictive of superior outcomes with EGFR tyrosine kinase ...inhibitors (TKIs). Eventually, acquired genetic or phenotypic resistance overcomes EGFR TKI therapy. Heterogeneity of acquired anti-EGFR resistance mechanisms is increasingly described, presenting a significant challenge in their clinical management. Here, we report a rare case of concurrent acquired EGFRT790M and small cell lung cancer transformation in a patient with EGFR exon 21-L858R mutant lung adenocarcinoma, following treatment with a second-generation EGFR TKI. The case highlights the clinical significance of serial EGFR genotyping with peripheral ctDNA alongside targeted biopsies, for the detection of genetic and phenotypic resistance mechanisms to EGFR TKIs, which can occur concurrently. This case provides further evidence in favour of upfront treatment approaches that target the heterogeneity of acquired anti-EGFR resistance mechanisms, such as experimental combinations of cytotoxic chemotherapy with a third-generation EGFR TKI.
Background
Myocardial programmed death-ligand 1 (PD-L1) expression is implicated in immune checkpoint inhibitor (ICI)-associated myocarditis. Measurement of myocardial PD-L1 expression may have ...potential use as a mechanistic and predictive biomarker. The aim of this study was to determine non-invasive assessment of myocardial PD-L1 expression using
99m
Tc-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT.
Methods
Thoracic
99m
TcNM-01 SPECT/CT was performed in lung cancer patients (
n
= 10) at baseline and 9-weeks following anti-programmed cell death protein 1 (PD-1) therapy. Baseline and 9-week left ventricular and right ventricular to blood pool ratios (LV
max
:BP) and (RV
max
:BP) were measured. LV
max
was compared to background skeletal muscle (muscle
max
). Intra-rater reliability was determined by intraclass correlation coefficient (ICC) and Bland–Altman analysis.
Results
Mean LV
max
:BP values were 2.76 ± 0.67 at baseline vs 2.55 ± 0.77 at 9 weeks (
p
= 0.42). Mean RV
max
:BP was 1.82 ± 0.32 at baseline vs 1.76 ± 0.45 at 9 weeks (
p
= 0.67). Myocardial PD-L1 expression was at least threefold greater than skeletal muscle at baseline for the LV (LV
max
to muscle
max
3.71 ± 0.77 vs 0.98 ± 0.20 (
p
< 0.001)) and at least twofold for the RV (LV
max
to muscle
max
2.49 ± 0.63 vs 0.98 ± 0.20 (
p
< 0.001)). There was excellent intra-rater reliability for LV
max
:BP with ICC 0.99 (95% confidence interval 0.94–0.99,
p
< 0.001), mean bias -0.05 ± 0.14 (95% limits of agreement -0.32 to 0.21). There were no major adverse cardiovascular events or myocarditis during follow-up.
Conclusion
This study is the first to report PD-L1 expression of the heart that can be quantified non-invasively without invasive myocardial biopsy, with high reliability and specificity. This technique can be applied to investigate myocardial PD-L1 expression in ICI-associated myocarditis and cardiomyopathies.
Clinical trial registration
PD-L1 Expression in Cancer (PECan) study (NCT04436406).
https://clinicaltrials.gov/ct2/show/NCT04436406
June 18th, 2020.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (
C9orf72)
have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be ...the most common genetic cause of both neurodegenerative diseases. Genetic variants at
TMEM106B
influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that
TMEM106B
is a genetic modifier of FTLD-TDP caused by progranulin (
GRN
) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with
C9orf72
expansions (
n
= 14), with the major allele correlated with later age at death (
p
= 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with
C9orf72
expansions (
n
= 75), again finding that the major allele associates with later age at death (
p
= 0.016), as well as later age at onset (
p
= 0.019). In contrast,
TMEM106B
genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for
GRN
mutations or
C9orf72
expansions. Thus,
TMEM106B
is a genetic modifier of FTLD with
C9orf72
expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in
C9orf72
expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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![[99mTc]-labelled anti-Progr...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2191-219X/small "[99mTc]-labelled anti-Programmed Death-Ligand 1 single-domain antibody SPECT/CT: a novel imaging biomarker for myocardial PD-L1 expression")
