On December 3, 2015 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported that its collaborator, Moffitt Cancer Center, will present preclinical data for its dual-targeting bromodomain (BRD) / kinase inhibitor, MA2-014, at the 57th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition being held December 5-8, 2015, in Orlando, FL (Press release, Aptose Biosciences, DEC 3, 2015, View Source;p=RssLanding&cat=news&id=2119892 [SID:1234508437]).

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The dual-targeting inhibitor MA2-014 is a representative candidate from a new family of small molecule, dual-targeting BRD / kinase inhibitors licensed to Aptose from Moffitt Cancer Center. The MA2-014 program was developed to inhibit both the bromodomain 4 (BRD4) protein and the Janus kinase 2 (JAK2) for the potential treatment of various hematologic and solid tumor cancers. The data being presented by Moffitt researchers reflect in vitro activity of MA2-014 in myeloproliferative neoplasm (MPN) cell lines. MPNs are rare blood cancers including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF).

Clinically, JAK2 inhibitors alone have demonstrated the ability to improve symptoms of MPNs, but have not been shown to induce remission. Further, combining a bromodomain inhibitor and a JAK2 inhibitor has been shown to be more effective against MPN cells than JAK2 inhibition alone. This provided rationale to develop a single molecule with potent activity against both the bromodomain family proteins and JAK2. Moffitt researchers will present data for MA2-014, a single molecule that exhibits similar anti-JAK2 activity as a known JAK2 inhibitor, TG101209, with an approximate ten-fold improvement in anti-BRD activity. Moffitt researchers also demonstrated a ten-fold improvement in the ability of MA2-014 to inhibit JAK2-V617F signaling over TG101209, and comparable to ruxolitinib. Ruxolitinib is the only FDA approved JAK inhibitor for MPNs. However, MA2-014 retained its potency against ruxolitinib-resistant cells. Moffitt researchers also determined in long-term culture assays that JAK2-V617F driven MPN Uke1 cells do not experience resistance to MA2-014 as readily as they do to TG101209 or ruxolitinib.

"We are excited to continue development of MA2-014 and other candidates in our collaboration with Moffitt and to advance highly differentiated dual-targeting BRD / kinase inhibitors for the treatment of rare blood cancers into the clinic," said William G. Rice, Ph.D., Chairman, President and CEO. "We share Moffitt’s optimism about the potential for dual-targeting BRD / kinase inhibitors as high-value epigenetic drug candidates to provide the benefits of combination therapy for hematologic cancers."

"The development and optimization of a single drug designed to simultaneously inhibit JAK2 kinase and bromodomains of the bromodomain and extraterminal proteins may improve therapy for myeloproliferative neoplasms (MPN), by delivering a potentially effective combination therapy with a single agent," said Gary Reuther, Associate Member of the Cancer Biology and Evolution Program at Moffitt. "Such dual inhibition of these targets and their respective pathways may provide a new effective MPN therapy and reduce the development of drug resistance seen with JAK2 inhibitors."

Abstract Details

Title: "Single Molecule Dual JAK2-BET Inhibition as an MPN Therapeutic"
* Date/Time: Sunday, December 6, 2015, 6:00 – 8:00 p.m.
* Location: Orange County Convention Center, Hall A, Level 2
* Abstract #: 2826
* Session: 635. Myeloproliferative Syndromes: Basic Science: Poster II

The abstract is available in the online edition of Blood, the official Journal of the American Society of Hematology (ASH) (Free ASH Whitepaper) and on the ASH (Free ASH Whitepaper) conference website.

Aptose previously announced additional ASH (Free ASH Whitepaper) abstracts on its lead clinical candidate APTO-253:

Title: "Broad Activity of APTO-253 in AML and Other Hematologic Malignancies Correlates with KLF4 Expression Level"
* Date/Time: Saturday, December 5, 2015, 5:30-7:30 p.m.
* Location: Orange County Convention Center, Hall A
* Abstract #: 83676
* Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I

Title: "Clinical Pharmacokinetics of APTO-253 Support its Use as a Novel Agent for the Treatment of Relapsed or Refractory Hematologic Malignancies"
* Abstract #: 4934
* Location: Publication

Strategic Collaboration with Moffitt Cancer Center

Aptose recently entered into a definitive agreement with Moffitt Cancer Center for exclusive global rights to potent, multi-targeting, single-agent inhibitors for the treatment of hematologic and solid tumor cancers. These small molecule agents are highly differentiated inhibitors of the Bromodomain and Extra-Terminal motif (BET) protein family members, which simultaneously target specific kinase enzymes. The molecules developed by Moffitt exhibit single-digit nanomolar potency against the BET family members and specific oncogenic kinases which, when inhibited, are synergistic with BET inhibition. Under the agreement, Aptose gains access to the drug candidates developed by Moffitt and the underlying intellectual property covering the chemical modifications enabling potent bromodomain (BRD) inhibition on the chemical backbone of a kinase inhibitor. Aptose expects lead clinical candidates to emerge from the collaboration by late 2016.