JNJ-26481585

JNJ-26481585 is a novel histone deacetylase (HDAC) inhibitor that exerts a strong potency towards class I HDAC (including HDAC1, HDAC2 and HDAC3), with values of inhibition constant IC₅₀ of 0.11, 0.33 and 4.8 nmol/L respectively, leading to strong anti-proliferative activities (IC₅₀ ranging from 3.1 to 246 nmol/L) against a broad range of cancer cell lines including lung, breast, colon, prostate, brain and overian cancer cell lines. Recent study results have shown that JNJ-26481585 strongly induce the HDAC1-suppressed p21^waf1,cip1 promoter in vivo, histone H3 acetylation in tumor tissue and apoptosis in human colon cancer cell lines (both APC wild-type and mutant) in vitro.

Reference

Arts J, King P, Mariën A, Floren W, Beliën A, Janssen L, Pilatte I, Roux B, Decrane L, Gilissen R, Hickson I, Vreys V, Cox E, Bol K, Talloen W, Goris I, Andries L, Du Jardin M, Janicot M, Page M, van Emelen K, Angibaud P. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res. 2009;15(22):6841-6851

Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program.[Pubmed:24038993]

Pediatr Blood Cancer. 2014 Feb;61(2):245-52.

BACKGROUND: Quisinostat (JNJ-26481585) is a second-generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs. PROCEDURES: Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 muM and was tested against the PPTP in vivo panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily x 21. RESULTS: In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2 nM (range <1-19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease. CONCLUSIONS: Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts.

Effect of histone deacetylase inhibitor JNJ-26481585 in pain.[Pubmed:25085711]

J Mol Neurosci. 2015 Mar;55(3):570-8.

Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585-treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose- and time-dependent activation of nuclear factor-kappaB and interleukin-1beta increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin.

Critical role of mitochondria-mediated apoptosis for JNJ-26481585-induced antitumor activity in rhabdomyosarcoma.[Pubmed:26616861]

Oncogene. 2016 Jul 14;35(28):3729-41.

JNJ-26481585 is a second-generation histone deacetylase inhibitor with broad-range efficacy and improved pharmacodynamic properties. In the present study, we investigated the therapeutic potential of JNJ-26481585 and its molecular mechanisms of action in rhabdomyosarcoma (RMS). Here, we report that JNJ- 26481585's anticancer activity critically depends on an intact mitochondrial pathway of apoptosis. JNJ-26481585 induces apoptosis and also inhibits long-term clonogenic survival of several RMS cell lines at nanomolar concentrations that cause histone acetylation. Importantly, JNJ-26481585 significantly suppresses tumor growth in vivo in two preclinical RMS models, that is, the chorioallantoic membrane model and a xenograft mouse model. Mechanistically, we identify activation of the mitochondrial pathway of apoptosis as a key event that is critically required for JNJ-26481585-mediated cell death. JNJ-26481585 upregulates expression levels of several BH3-only proteins including Bim, Puma and Noxa, which all contribute to JNJ-26481585-mediated apoptosis, as knockdown of Bim, Puma or Noxa significantly inhibits cell death. This shift toward proapoptotic Bcl-2 proteins promotes activation of Bax and Bak as a critical event, as genetic silencing of Bax or Bak protects against JNJ-26481585-induced apoptosis. Intriguingly, rescue experiments reveal that JNJ-26481585 triggers Bax/Bak activation independently of caspase activation and activates caspase-9 as the initiator caspase in the cascade, as Bcl-2 overexpression, but not the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) blocks JNJ-26481585-induced Bax/Bak activation and caspase-9 cleavage. In conclusion, JNJ-26481585 exerts potent antitumor activity against RMS in vitro and in vivo by engaging mitochondrial apoptosis before caspase activation and represents a promising therapeutic for further investigation in RMS.

JNJ-26481585 primes rhabdomyosarcoma cells for chemotherapeutics by engaging the mitochondrial pathway of apoptosis.[Pubmed:26473375]

Oncotarget. 2015 Nov 10;6(35):37836-51.

Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma in childhood with a poor prognosis, highlighting the need for new treatment strategies. Here we identify a synergistic interaction of the second-generation histone deacetylase inhibitor (HDACI) JNJ-26481585 and common chemotherapeutic drugs (i.e. Doxorubicin, Etoposide, Vincristine, Cyclophosphamide and Actinomycin D) to trigger apoptosis in RMS cells. Importantly, JNJ-26481585/Doxorubicin cotreatment also significantly suppresses long-term clonogenic survival of RMS cells and tumor growth in vivo in a preclinical RMS model. Mechanistically, JNJ-26481585/Doxorubicin cotreatment causes upregulation of the BH3-only proteins Bim and Noxa as well as downregulation of the antiapoptotic proteins Mcl-1 and Bcl-xL. These changes in the ratio of pro- and antiapoptotic Bcl-2 proteins contribute to JNJ-26481585/Doxorubicin-mediated apoptosis, since knockdown of Bim or Noxa significantly inhibits cell death. Also, JNJ-26481585 and Doxorubicin cooperate to stimulate activation of Bax and Bak, which is required for JNJ-26481585/Doxorubicin-induced apoptosis, since silencing of Bax or Bak protects against apoptosis. Consistently, overexpression of Bcl-2 significantly reduces JNJ-26481585/Doxorubicin-mediated apoptosis. JNJ-26481585/Doxorubicin cotreatment leads to caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) rescues cells from apoptosis. In conclusion, the second-generation HDACI JNJ-26481585 cooperates with chemotherapeutics to engage mitochondrial apoptosis in RMS cells, demonstrating that JNJ-26481585 represents a promising strategy for chemosensitization of RMS.