Abstract 2590: KD019: Blood brain barrier penetrant HER2/neu, Src, and EGFR inhibitor
Authors: Tonra James R. , Poyurovsky Masha , Liu Kevin G. , Patel Jeegar , Rao Nishta , Tilton Robert , Ryan John L. , Berger Mark S. , Witte Larry , Kim Ji-In , Waksal Samuel D. 
Published: August 2015

Abstract
KD019 is an orally bioavailable small molecule inhibitor of molecular drivers of cancer growth and progression, including HER2/neu, Src family nonreceptor tyrosine kinases (Src) and EGFR. This profile of activity underlies the robust activity of KD019 in animal models of cancer. Although alternative agents targeting these tyrosine kinase receptors are available, only KD019 targets all of these pathways without the need for a combination strategy. A more important shortcoming of alternative agents is a lack of blood brain barrier (BBB) penetration (Brain/Plasma concentration ratio&lt;&lt;1), significantly limiting their ability to target oncogenic molecular pathways in intracranial tumors. The BBB permeability of KD019 was heretofore untested.
In the present work, KD019 is demonstrated to achieve concentrations in the brain equivalent to that in blood utilizing quantitative whole body autoradiography (QWBA). Lister Hooded partially pigmented rats were administered a single dose of 14C labeled KD019 and tissue radioactivity was evaluated utilizing phosphor-storage imaging plates and a Fuji FLA-5100 fluorescent image analyzing system (Quotient Bioresearch, Rushden, UK). Brain/blood radioactivity ratio was approximately 1 at 6-24 hours after dosing indicating significant brain penetration of KD019. BBB penetrance was further supported by a study performed in CD1 mice utilizing LC/MS/MS to determine tissue KD019 concentrations following a single oral dose of 100 mg free base/kg unlabeled drug (Pharmaron, Beijing, China). Brain/plasma KD019 ratios were 2.3-4.4 from 1-24 hours after dosing with brain concentrations of 2137-8253 ng/g tissue, compared to 0.03-0.07 for the EGFR/HER2 inhibitor lapatinib with brain concentrations of 0-286 ng/g tissue. To demonstrate that the penetration of KD019 into the brain parenchyma would translate into anticancer effects, KD019 efficacy was tested in a GL261 orthotopic syngeneic model of glioma (Molecular Imaging, Michigan, USA). GL261-luc2 luciferase expressing cells were implanted intracranially (2 mm right lateral and 1 mm anterior from Bregma, 2-3 mm down from burr hole) into C57BL/6 albino mice. KD019 dosed orally once daily at 75 mg base/kg on Days 8-12 and 15-19 after intracranial implantation significantly reduced the intracranial tumor growth as evaluated by bioluminescence, and extended median survival time by 20%.
In conclusion, KD019 is a BBB penetrant TKI with an important and novel profile of kinase activity that, based on the data presented, will be advanced further in nonclinical and clinical experiments aiming at benefiting patients with intracranial tumors, a significant unmet clinical need. KD019 is currently being tested in combination with trastuzumab in patients with HER2-positive breast cancer and brain metastases.
Citation Format: James R. Tonra, Masha Poyurovsky, Kevin G. Liu, Jeegar Patel, Nishta Rao, Robert Tilton, John L. Ryan, Mark S. Berger, Larry Witte, Ji-In Kim, Samuel D. Waksal. KD019: Blood brain barrier penetrant HER2/neu, Src, and EGFR inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2590. doi:10.1158/1538-7445.AM2015-2590