On December 1, 2016 Kura Oncology, Inc. (Nasdaq:KURA), a clinical stage biopharmaceutical company, reported preclinical data highlighting the identification and characterization of KO-947, its development candidate targeting ERK1/2 kinases (Press release, Kura Oncology, DEC 1, 2016, View Source [SID1234516867]). The company has also presented preclinical data relating to the identification and optimization of potent and selective inhibitors of the menin-MLL interaction. Both presentations took place at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics (EORTC) in Munich, Germany. Schedule your 30 min Free 1stOncology Demo! "We are excited to present preclinical data from these two innovative programs at EORTC, both of which showed compelling activity in preclinical models of cancer," said Yi Liu, Ph.D., Chief Scientific Officer. "Looking forward, we anticipate nominating a development candidate for our menin-MLL program by the end of 2016, and initiating a Phase 1 clinical trial for KO-947 in the first half of 2017."
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KO-947 – A potent and selective inhibitor of ERK1/2 kinases
The RAS/RAF/MEK pathway is estimated to be activated in more than 30% of human cancers, including cancers arising from mutations in KRAS, NRAS and BRAF. Although inhibitors of both BRAF and MEK have been approved for treatment of melanoma, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples due to reactivation of ERK1/2 kinases.
In preclinical studies presented today at EORTC, KO-947 showed potent inhibition of ERK signaling pathways and proliferation of tumor cells exhibiting dysregulation of MAPK pathway, including mutations in BRAF, NRAS or KRAS. KO-947 also inhibits MAPK signaling and cell proliferation in preclinical models that are resistant to BRAF and MEK inhibitors. Results obtained from screening a large panel of PDX models demonstrate that KO-947 induces tumor regressions in BRAF or RAS mutated tumor models as well as in tumor models lacking BRAF/RAS mutations but characterized by other dysregulation of the MAPK pathway.
KO-947 appears to be differentiated from other published ERK inhibitors by an extended residence time and prolonged pathway inhibition in vitro and in vivo. The data further suggest that the drug properties of KO-947 may allow Kura to maximize the therapeutic window with flexible administration routes and schedules, including intermittent dosing.
Inhibitors of the Menin-MLL Interaction
Chromosomal translocations that affect the mixed lineage leukemia (MLL) gene result in aggressive acute myeloid and lymphoid leukemias that are often resistant to standard chemotherapy. Approximately 5-10% of acute leukemias in adults, and 70% of acute leukemias in infants, are characterized by tumors with abnormal MLL fusions. MLL fusion proteins require menin for leukemogenic activity and selective disruption of the menin-MLL interaction represents a potential therapeutic approach for the treatment of acute leukemias with MLL rearrangements.
In preclinical studies presented at EORTC, inhibitors of the menin-MLL interaction showed potent inhibition of the proliferation of MLL leukemic cells. Inhibitors of the menin-MLL interaction displayed a greater than 50-fold reduction in potency in non-MLL-fusion leukemia cell lines and induced regression in a MV4:11 mouse xenograft model. The data show that the anti-tumor activity of menin-MLL inhibitors correlates with target engagement in tumors as well as inhibition of expression of downstream genes under the regulation of the fusion protein. Moreover, the inhibitors demonstrated potent efficacy in subcutaneous and disseminated models of MLL-fusion leukemias.
Both of the posters presented at EORTC can be found on Kura’s website in the Scientific Presentations and Papers section or by clicking here.