Purpose: This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph þ B-cell acute lymphoblastic leukemia (B-ALL).Experimental Design: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph þ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph þ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)-induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph þ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph þ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate.
Results: Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph þ leukemia cell lines and primary Ph þ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph þ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph þ B-ALL, BCR-ABL(T315I)-induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph þ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.Conclusions: Purinostat mesylate provides a new therapeutic strategy for patients with Ph þ B-ALL, including those who relapse after TKI treatment.
In
this study, we described a series of 2,8-diazaspiro[4.5]decan-1-one
derivatives as selective TYK2/JAK1 inhibitors. Systematic exploration
of the structure–activity relationship through the introduction
of spirocyclic scaffolds based on the reported selective TYK2 inhibitor 14l led to the discovery of the superior derivative compound 48. Compound 48 showed excellent potency on TYK2/JAK1
kinases with IC50 values of 6 and 37 nM, respectively,
and exhibited more than 23-fold selectivity for JAK2. Compound 48 also demonstrated excellent metabolic stability and more
potent anti-inflammatory efficacy than tofacitinib in acute ulcerative
colitis models. Moreover, the excellent anti-inflammatory effect of
compound 48 was mediated by regulating the expression
of related TYK2/JAK1-regulated genes, as well as the formation of
Th1, Th2, and Th17 cells. Taken together, these findings suggest that
compound 48 is a selective dual TYK2/JAK inhibitor, deserving
to be developed as a clinical candidate.
So far, relatively few small molecules
have been reported to promote
tubulin degradation. Our previous studies have found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting
αβ-tubulin degradation. To further improve its antiproliferative
activity, 66 derivatives or analogues of 2 were designed
and synthesized based on 2-tubulin cocrystal structure.
Among them, 12b displayed nanomolar potency against a
variety of tumor cells, including paclitaxel- and adriamycin-resistant
cell lines. 12b binds to the colchicine site and promotes
αβ-tubulin degradation in a concentration-dependent manner
via the ubiquitin–proteasome pathway. The X-ray crystal structure
revealed that 12b binds in a similar manner as 2, but there is a slight conformation change of the B ring,
which resulted in better interaction of 12b with surrounding
residues. 12b effectively suppressed tumor growth at
an i.v. dose of 40 mg/kg (3 times a week) on both A2780S (paclitaxel-sensitive)
and A2780T (paclitaxel-resistant) ovarian xenograft models, with respective
TGIs of 92.42 and 79.75% without obvious side effects, supporting
its potential utility as a tumor-therapeutic compound.
Post-myocardial infarction heart failure (post-MI HF) is one of the leading global causes of death, and current prevention and treatment methods still cannot avoid the increasing incidence. Honokiol (HK) has previously been reported to improve myocardial ischemia/reperfusion injury and reverse myocardial hypertrophy by activating Sirt1 and Sirt3. We suspect that HK may also have a therapeutic effect on post-MI HF. In this study, we aimed to investigate the efficacy and mechanism of HK in the treatment of post-MI HF. We found that HK inhibited myocardial reactive oxygen species (ROS) production, reduced myocardial fibrosis, and improved cardiac function in mice after MI. HK also reduced the abnormality of mitochondrial membrane potential (MMP) and apoptosis of cardiomyocytes caused by peroxide in neonatal cardiomyocytes. RNAseq results revealed that HK restored the transcriptome changes to a certain extent and significantly enhanced the expression of mitochondrial inner membrane uncoupling protein isoform 3 (Ucp3), a protein that inhibits the production of mitochondrial ROS, protects cardiomyocytes, and relieves heart failure after myocardial infarction (MI). In cardiomyocytes with impaired Ucp3 expression, HK cannot protect against the damage caused by peroxide. More importantly, in Ucp3 knockout mice, HK did not change the increase in the ROS level and cardiac function damage after MI. Taken together, our results suggest that HK can increase the expression of the cardioprotective protein Ucp3 and maintain MMP, thereby inhibiting the production of ROS after MI and ameliorating heart failure.
2021) A size-shrinkable matrix metallopeptidase-2-sensitive delivery nanosystem improves the penetration of human programmed death-ligand 1 siRNA into lung-tumor spheroids,
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