9 research outputs found
Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity
In our previous research, a series of phenylsulfonylfuroxan-based
hydroxamates were developed, among which compound 1 exhibited
remarkable in vitro and in vivo antitumor potency due to its histone
deacetylase (HDAC) inhibitory and nitric oxide (NO)-donating activities.
Herein, the in-depth study of compound 1 revealed that
this HDAC inhibitor-NO donor hybrid could enduringly increase the
intracellular levels of acetyl histones and acetyl α-tubulin,
which could be ascribed to its irreversible inhibition toward class
I HDACs and HDAC6. Structural modification of compound 1 led to a novel phenylsulfonylfuroxan-based hydroxamate 4, which exhibited considerable HDAC6 inhibitory activity and selectivity.
Furthermore, compound 4 could inhibit intracellular HDAC6
both selectively and irreversibly. To the best of our knowledge, this
is the first research reporting the irreversible inhibition of HDAC6.
It was also demonstrated that compared with ACY-241 (a reversible
HDAC6 inhibitor in clinical trials), the irreversible HDAC6 selective
inhibitor 4 exhibited not only superior anti-multiple
myeloma activity but also improved therapeutic index
Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity
In our previous research, a series of phenylsulfonylfuroxan-based
hydroxamates were developed, among which compound 1 exhibited
remarkable in vitro and in vivo antitumor potency due to its histone
deacetylase (HDAC) inhibitory and nitric oxide (NO)-donating activities.
Herein, the in-depth study of compound 1 revealed that
this HDAC inhibitor-NO donor hybrid could enduringly increase the
intracellular levels of acetyl histones and acetyl α-tubulin,
which could be ascribed to its irreversible inhibition toward class
I HDACs and HDAC6. Structural modification of compound 1 led to a novel phenylsulfonylfuroxan-based hydroxamate 4, which exhibited considerable HDAC6 inhibitory activity and selectivity.
Furthermore, compound 4 could inhibit intracellular HDAC6
both selectively and irreversibly. To the best of our knowledge, this
is the first research reporting the irreversible inhibition of HDAC6.
It was also demonstrated that compared with ACY-241 (a reversible
HDAC6 inhibitor in clinical trials), the irreversible HDAC6 selective
inhibitor 4 exhibited not only superior anti-multiple
myeloma activity but also improved therapeutic index
A Closed-Loop Process for Selective Metal Recovery from Spent Lithium Iron Phosphate Batteries through Mechanochemical Activation
With the increasing
consumption of lithium ion batteries (LIBs)
in electric and electronic products, the recycling of spent LIBs has
drawn significant attention due to their high potential of environmental
impacts and waste of valuable resources. Among different types of
spent LIBs, the difficulties for recycling spent LiFePO<sub>4</sub> batteries rest on their relatively low extraction efficiency and
recycling selectivity in which secondary waste is frequently generated.
In this research, mechanochemical activation was developed to selectively
recycle Fe and Li from cathode scrap of spent LiFePO<sub>4</sub> batteries.
By mechanochemical activation pretreatment and the diluted H<sub>3</sub>PO<sub>4</sub> leaching solution, the leaching efficiency of Fe and
Li can be significantly improved to be 97.67% and 94.29%, respectively.
To understand the Fe and Li extraction process and the mechanochemical
activation mechanisms, the effects of various parameters during Fe
and Li recovery were comprehensively investigated, including activation
time, cathode powder to additive mass ratio, acid concentration, the
liquid-to-solid ratio, and leaching time. Subsequently, the metal
ions after leaching can be recovered by selective precipitation. In
the whole process, about 93.05% Fe and 82.55% Li could be recovered
as FePO<sub>4</sub>·2H<sub>2</sub>O and Li<sub>3</sub>PO<sub>4</sub>, achieving selective recycling of metals for efficient use
of resources from spent lithium ion batteries
Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer
Multitarget HDAC inhibitors capable of simultaneously
blocking
the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for
the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based
multitarget HDAC inhibitors were rationally designed, synthesized,
and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple
inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3
signaling pathway, which was validated by hyper-acetylation of histone
and α-tubulin, hypo-phosphorylation of STAT3, downregulation
of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects
of 25ap contributed to
its robust antitumor response, including potent antiproliferative
activity, remarkable apoptosis-inducing activity, and inhibition of
colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous
cells, desirable in vitro metabolic stability in mouse microsome,
and sufficient in vivo exposure via intraperitoneal administration.
Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft
model
Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer
Multitarget HDAC inhibitors capable of simultaneously
blocking
the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for
the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based
multitarget HDAC inhibitors were rationally designed, synthesized,
and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple
inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3
signaling pathway, which was validated by hyper-acetylation of histone
and α-tubulin, hypo-phosphorylation of STAT3, downregulation
of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects
of 25ap contributed to
its robust antitumor response, including potent antiproliferative
activity, remarkable apoptosis-inducing activity, and inhibition of
colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous
cells, desirable in vitro metabolic stability in mouse microsome,
and sufficient in vivo exposure via intraperitoneal administration.
Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft
model
Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer
Multitarget HDAC inhibitors capable of simultaneously
blocking
the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for
the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based
multitarget HDAC inhibitors were rationally designed, synthesized,
and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple
inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3
signaling pathway, which was validated by hyper-acetylation of histone
and α-tubulin, hypo-phosphorylation of STAT3, downregulation
of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects
of 25ap contributed to
its robust antitumor response, including potent antiproliferative
activity, remarkable apoptosis-inducing activity, and inhibition of
colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous
cells, desirable in vitro metabolic stability in mouse microsome,
and sufficient in vivo exposure via intraperitoneal administration.
Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft
model
Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer
Multitarget HDAC inhibitors capable of simultaneously
blocking
the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for
the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based
multitarget HDAC inhibitors were rationally designed, synthesized,
and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple
inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3
signaling pathway, which was validated by hyper-acetylation of histone
and α-tubulin, hypo-phosphorylation of STAT3, downregulation
of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects
of 25ap contributed to
its robust antitumor response, including potent antiproliferative
activity, remarkable apoptosis-inducing activity, and inhibition of
colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous
cells, desirable in vitro metabolic stability in mouse microsome,
and sufficient in vivo exposure via intraperitoneal administration.
Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft
model
Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer
Multitarget HDAC inhibitors capable of simultaneously
blocking
the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for
the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based
multitarget HDAC inhibitors were rationally designed, synthesized,
and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple
inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3
signaling pathway, which was validated by hyper-acetylation of histone
and α-tubulin, hypo-phosphorylation of STAT3, downregulation
of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects
of 25ap contributed to
its robust antitumor response, including potent antiproliferative
activity, remarkable apoptosis-inducing activity, and inhibition of
colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous
cells, desirable in vitro metabolic stability in mouse microsome,
and sufficient in vivo exposure via intraperitoneal administration.
Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft
model
Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer
Multitarget HDAC inhibitors capable of simultaneously
blocking
the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for
the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based
multitarget HDAC inhibitors were rationally designed, synthesized,
and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple
inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3
signaling pathway, which was validated by hyper-acetylation of histone
and α-tubulin, hypo-phosphorylation of STAT3, downregulation
of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects
of 25ap contributed to
its robust antitumor response, including potent antiproliferative
activity, remarkable apoptosis-inducing activity, and inhibition of
colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous
cells, desirable in vitro metabolic stability in mouse microsome,
and sufficient in vivo exposure via intraperitoneal administration.
Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft
model