Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies

Abstract

Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-aminopyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2 V617F mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.

Computational Study of Pyrimidin‐2‐Aminopyrazol‐Hydroxamate‐based JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

“…The data set of 29 pyrimidin‐2‐aminopyrazol‐hydroxamate JAK2 inhibitors was used for the modeling study . The compounds were sketched and energy minimized using Sybyl‐X 2.1.…”

“…3D‐QSAR study was performed based on the 29 pyrimidin‐2‐aminopyrazol‐hydroxamate JAK2 inhibitors reported by Liang et al . The compounds and their corresponding activity values (pIC 50 ) were shown in Table .…”

“…We have performed computational studies on a data set of 29 pyrimidin‐2‐aminopyrazol hydroxamate derivatives which showed inhibitory activity for JAK2 . 3D‐QSAR model was developed based on comparative molecular field analysis (CoMFA) descriptors.…”

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

“…In analogous studies by three independent groups, the hybrids 20 – 22 were also shown to display dual JAK/HDAC inhibition with a degree of selectivity towards HDAC6 [ 144 , 145 , 146 ]. Alike pacritinib in the synthesis of 19 , each work utilised a JAK (or JAK2-selective) inhibitor containing an aminopyrimidine unit flanked by two hydrophobic aromatic groups—crucial for binding to the hinge region of the JAK active site.…”

Design, Synthesis and Biological Evaluation of Novel Benzoylimidazole Derivatives as Raf and Histone Deacetylases Dual Inhibitors

“…A lot of literatures have described the synergistic and additive effects by the joint use of HDACs inhibitors and vari-ous antitumor agents. [13][14][15] Recently, Emmons et al revealed that HDACs inhibitor could enhance the durability of BRaf inhibitor therapy. 16) Hence, the development of BRaf V600E and HDACs dual inhibitors maybe a valuable strategy to circumvent resistance.…”