Abstract C187: Cross-inhibition of Trk receptors by TAS-119, a novel Aurora A selective inhibitor, exhibits therapeutic potential in a Trk-driven cancer model

AbstractDespite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.

Download Full-text

279 POSTER MLN8054, a selective inhibitor of Aurora A kinase: final results of a phase I clinical trial

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)72213-4 ◽

2008 ◽

Vol 6 (12) ◽

pp. 90 ◽

Cited By ~ 2

Author(s):

A. Cervantes ◽

T. Macarulla ◽

S. Roselló ◽

E. Rodríguez-Braun ◽

J. Baselga ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Selective Inhibitor ◽

Phase I Clinical Trial ◽

Aurora A Kinase ◽

Aurora A

Download Full-text

281 POSTER Phase I and pharmacokinetic study of MLN8054, a selective inhibitor of Aurora A kinase

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)72215-8 ◽

2008 ◽

Vol 6 (12) ◽

pp. 91 ◽

Cited By ~ 2

Author(s):

E. Dees ◽

J.R. Infante ◽

R.B. Cohen ◽

B. O'Neil ◽

H. Burris ◽

...

Keyword(s):

Phase I ◽

Pharmacokinetic Study ◽

Selective Inhibitor ◽

Aurora A Kinase ◽

Aurora A

Download Full-text

Discovery of an MLLT1/3 YEATS Domain Chemical Probe

10.26434/chemrxiv.7090547 ◽

2018 ◽

Cited By ~ 1

Author(s):

Moses Moustakim ◽

Thomas Christott ◽

Octovia P. Monteiro ◽

James Bennett ◽

Charline Giroud ◽

...

Keyword(s):

Drug Discovery ◽

Crystal Structures ◽

Small Molecule ◽

Therapeutic Potential ◽

Selective Inhibitor ◽

Target Engagement ◽

Chemical Probe ◽

X Ray ◽

Cellular Target ◽

Excellent Selectivity

<p>YEATS domain (YD) containing proteins are an emerging</p> <p>class of epigenetic targets in drug discovery. Dysregulation of these modified lysine binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3 -histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first in class probe molecule can be used to understand MLLT1/3 associated biology and the therapeutic potential of small molecule YD inhibitors.</p>

Download Full-text

A selective adenylyl cyclase 1 inhibitor relieves pain without causing tolerance

10.1101/2021.06.23.448127 ◽

2021 ◽

Author(s):

Gianna Giacoletti ◽

Tatum Price ◽

Lucas V. B. Hoelz ◽

Abdulwhab Shremo Msdi ◽

Katerina Vazquez-Falto ◽

...

Keyword(s):

Visceral Pain ◽

Therapeutic Potential ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Selective Inhibitor ◽

Adenylyl Cyclases ◽

Analgesic Tolerance ◽

Relieve Pain ◽

Analgesic Agents ◽

Knockout Animals

Adenylyl cyclases (ACs) catalyze the production of the second messenger cyclic adenosine monophosphate from adenosine triphosphate. Among the ten different AC isoforms, studies with knockout animals indicate that inhibition of AC1 can relieve pain and reduce behaviors linked to opioid dependence. We previously identified ST034307 as a selective inhibitor of AC1. The development of an AC1-selective inhibitor now provides the opportunity to further study the therapeutic potential of inhibiting this protein in pre-clinical animal models of pain and related adverse reactions. In the present study we have shown that ST034307 relieves pain in mouse models of formalin-induced inflammatory pain, acid-induced visceral pain, and acid-depressed nesting. In addition, ST034307 did not cause analgesic tolerance after chronic dosing. We also show that the compound is restricted to the periphery following subcutaneous injections and report the predicted molecular interaction between ST034307 and AC1. Our results indicate that AC1 inhibitors represent a promising new class of analgesic agents that treat pain and appear to produce less adverse effects than currently-used opioids.

Download Full-text