Abstract LB-A27: A novel small molecule menin-MLL inhibitor for potential treatment of MLL-rearranged leukemias and NPM1/DNMT3A-mutant AML
Authors: Burrows Francis , Wu Tao , Kessler Linda , Li Shuangwei , Zhang Jingchuan , Zarrinkar Patrick , Li Liansheng , Cierpicki Tomasz , Grembecka Jolanta , Ren Pingda , Liu Yi 
Published: August 2018

Abstract
Patients with MLL-rearranged leukemia typically have a poor prognosis and no targeted therapies are yet available. As the leukemogenic activity of MLL fusion proteins has been shown to be dependent on their direct interaction with menin, development of small molecules that block the menin-MLL interaction is a promising therapeutic strategy for this disease. In addition, recent reports have implicated menin-MLL signaling in some forms of MLL wild-type AML, including those bearing oncogenic mutations in NPM1 and DNMT3A, which together represent 45% of cases of AML, suggesting that menin-MLL inhibitors could provide clinical benefit in a broader population of AML patients than originally envisioned. We have recently reported a novel, potent, and selective small molecule menin-MLL inhibitor, KO-539, that effectively treats MLL leukemias in in vivo models, demonstrating its potential clinical utility. The compound potently inhibits the growth of MLL-rearranged cell lines, displays favorable PK properties, and is remarkably effective in a subcutaneous MV4;11 xenograft model. In both the MV4;11 and MOLM13 disseminated leukemia models, the compound confers a prolonged survival benefit compared to vehicle or the Phase III-stage FLT3 inhibitor quizartinib when dosed orally daily at well-tolerated doses. To extend the characterization of the compound to additional mutationally-defined subsets of AML, the activity of KO-539 was compared to quizartinib in two disseminated patient-derived xenograft (PDX) models of AML. In two independent studies in an NPM1mut/DNMT3Amut/FLT3-ITD model, animals received daily oral treatment KO-539, and tumor progression was monitored by weekly sampling and multiparameter FACS analysis of circulating human blasts, with similar analysis of bone marrow and spleen at sacrifice. All vehicle treated animals displayed progressive leukemia and died between 15 and 25 days after initiation of therapy with bone marrow completely comprised of undifferentiated CD45/CD38+ blasts and grossly enlarged spleens. By contrast, all animals treated with KO-539 were cleared of detectable leukemia by Day 28 and, in the 40% surviving animals in the first study, leukemia was not detectable even four weeks after cessation of therapy. Interestingly, those KO-539-treated animals that did succumb were found to have normal spleen weight and bone marrow that contained only differentiated CD11b+ human monocytes, suggesting that the compound was pharmacologically effective in all animals. This finding was confirmed in the repeat study, where therapy was initiated a few days earlier and all animals had no detectable tumors two months later. By contrast, quizartinib-treated animals initially responded well but relapsed while on treatment. Importantly, these results were confirmed in a second NPM1mut/DNMT3A-WT/FLT3 mut PDX model, where vehicle-treated animals succumbed by Day 35 and quizartinib-treated animals relapsed with progressive leukemia around the same time, but no evidence of disease progression was evident in the KO-539 group after 56 days. We describe a menin-MLL inhibitor with optimized drug-like properties that demonstrates potential clinical utility in preclinical models of MLL-rearranged and NPM1/DNMT3A/FLT3-mutant acute myeloid leukemias. The compound is currently undergoing further preclinical evaluation.
Citation Format: Francis Burrows, Tao Wu, Linda Kessler, Shuangwei Li, Jingchuan Zhang, Patrick Zarrinkar, Liansheng Li, Tomasz Cierpicki, Jolanta Grembecka, Pingda Ren, Yi Liu. A novel small molecule menin-MLL inhibitor for potential treatment of MLL-rearranged leukemias and NPM1/DNMT3A-mutant AML [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A27.