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JAK Bipasa
JAK Bipasa
agents
Introduction
Single Inhibitors
HDAC inhibitors JAK inhibitor
CHALLENGES
Drug resistance
The Need
Restriction to Multi- Cancers are heterogeneous and driven by multiple
haematological target genetic abnormalities. Two or multiple targets are
malignancies necessary to fight against malignant cancers
Introduction
• Multidrug-resistant cells have a higher activity of JAK/STAT signaling and an increased autocrine production of
STAT3-dependent cytokines than chemosensitive cells as shown in Fig.1 (Campia et al., 2015)
• HDAC inhibitors downregulated the expression of JAK2 V617F mutation protein and suppressed downstream
signaling to selectively influence the proliferation and growth of tumor cells bearing the JAK2 V617F mutation
over normal cells (Bareng et al., 2007)
• HDAC inhibitors were reported to downregulate STATs levels (Cardama et al., 2012)
• HDAC inhibitor could degrade proteasomal of JAK2 chaperone client oncoproteins to induce leukemic cell
apoptosis and demonstrated clinical benefits in AML but only acquired moderate efficacy as a single agent
(Buchwald et al., 2010)
• A phase Ib trial of Ruxolitinib in combination with Panabinostat to treat patients with MF showed good tolerance
and significant relief of symptoms, demonstrating great potential therapeutic value for treating MPNs
(NCT01433445 and NCT01693601) (Harrison et al., 2015)
• A combination of Pacritini and HDAC inhibitor Pracinostat substantiated synergistic antitumor effects in Fig. 1: western blot
preclinical mouse models of AML, implying the possible clinical application of simultaneous inhibition on JAK displaying overexpression of
JAK1 in A549/dx (resistant
and HDAC strategy for AML (Diermayr et al., 2012) cell line) compared to
chemosensitive cell line.
JAK-HDAC
Dual Inhibitors
Hypothesis
SAHA
Momelotinib
MS-275
Flow
cytometry
4. Drug Synthesis /
JAK-HDAC Characterisation
inhibitor
3.In-silico studies 7
Expected Outcomes/ Conclusion
In- • Docking and molecular dynamic simulation will predict the test compound
silic binding to HDAC isoforms and JAK subtypes.
o
stud
ies