Abstract 3936: Orally bioavailable 'lymphatropic' kinase inhibitors (2022)

Abstract Cancer signaling pathways can readily adapt to evade therapy through intrinsic resistance or compensatory mechanisms driving a resistant state. The prominence of oncogenic kinase signaling in a multitude of cancer types has inspired development of molecularly targeted drugs, facilitating combination treatment strategies designed to overcome adaptations such as signaling crosstalk and activation of downstream effectors. Treatments using inhibitor combinations, however, remain a challenge as clinical trials have been fraught with dose-limiting toxicities. Avoidance of hepatic first-pass metabolism by transport and sequestration into mesenteric gastrointestinal lymphatic vessels may improve drug exposure and reduce dose-limiting toxicities often observed in combination therapy studies. Despite potential advantages, lymphatically directed kinase inhibitors have remained unexplored due in part to limited understanding of the physicochemical properties required for lymphatic uptake of small molecules. We demonstrate a first-in-class series of orally bioavailable small molecule kinase inhibitors which are intrinsically ‘lymphatropic’, undergoing lymphatic absorption to achieve sustained circulatory drug levels and therapeutic benefit, with no observable toxicity. Single agent multifunctional inhibitors of high-value targets (MEK/PI3K, MEK/PI3K/mTOR, &amp; MEK/mTOR) were designed and synthesized. Compounds had unique physiochemical properties, demonstrating high lymphatic uptake in a mesenteric lymphatic vessel cannulation model and in isolated lymph nodes extracts. Pharmacokinetic studies in mice following oral administration revealed that sustained plasma blood levels were achieved within the therapeutic window for up to 24 hours. Oral bioavailability in mice was found to be 80-85% of drug administered and was constant over a single-dose range study (100 to 1,000 mg/kg). On-target in vitro and in vivo inhibition of activated MEK and PI3K was also demonstrated, revealing high potency of both the parent molecule and therapeutically active metabolites. Together, these studies revealed that lymphatic sequestration of orally dosed compounds serves to provide a reservoir that circumvents pharmacotoxicity through controlled physiological drug release into the systemic circulation and avoidance of first-pass hepatic metabolism. This platform provides a template for further development of additional lymphatropic small molecule inhibitors presenting opportunities in which multi-targeted cancer treatment options can now be evaluated. Exciting new therapeutic prospects offered by lymphatropic agent development is anticipated to transform treatment options for a wide variety of cancer types such as metastasis and lymphoma along with a myriad of other diseases including autoimmune disorders. Citation Format: Brian D. Ross, Youngsoon Jang, Amanda Welton, Christopher A. Bonham, Kevin Heist, Lucas McDonald, Gary D. Luker, Thomas L. Chenevert, Marcian Van Dort. Orally bioavailable 'lymphatropic' kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3936.