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

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-amino-pyrazol
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 JAK2V617F 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.