Elevated ocular VEMP responses in the absence of a superior semicircular canal dehiscence.

BACKGROUND: Vestibular evoked myogenic potentials (VEMPs) have an accepted role in the diagnosis of the superior semicircular canal dehiscence (SSCD) syndrome. The current impression is that ocular VEMPs (oVEMPs) are more sensitive than cervical VEMPs (cVEMPs) for detecting a SSCD and that oVEMP testing in response to air conducted sound provides an excellent screening test without risk of radiation exposure from computerized tomography (CT). AIMS/OBJECTIVES: To report on patients with elevated oVEMP amplitudes but without evidence for a SSCD on multiplanar CT imaging. MATERIAL AND METHODS: Retrospective chart review of all patients referred for vestibular function testing to our department. Patients with oVEMP peak-to-peak amplitudes ≥17 µν without evidence for a SSCD on imaging were evaluated. RESULTS: 26 patients had oVEMP peak-to-peak amplitudes ≥17 µν with no evidence of a SSCD on imaging. The most common diagnosis was Meniere's disease in those identified. CONCLUSION AND SIGNIFICANCE: oVEMPs can provide false positive results for diagnosis of a SSCD and an elevated oVEMP amplitude in itself is insufficient for diagnosis of a SSCD.

Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression.

Targeting the menin-MLL protein-protein interaction is being pursued as a new therapeutic strategy for the treatment of acute leukemia carrying MLL-rearrangements (MLLr leukemia). Herein, we report M-1121, a covalent and orally active inhibitor of the menin-MLL interaction capable of achieving complete and persistent tumor regression. M-1121 establishes covalent interactions with Cysteine 329 located in the MLL binding pocket of menin and potently inhibits growth of acute leukemia cell lines carrying MLL translocations with no activity in cell lines with wild-type MLL. Consistent with the mechanism of action, M-1121 drives dose-dependent down-regulation of HOXA9 and MEIS1 gene expression in the MLL-rearranged MV4;11 leukemia cell line. M-1121 is orally bioavailable and shows potent antitumor activity in vivo with tumor regressions observed at tolerated doses in the MV4;11 subcutaneous and disseminated models of MLL-rearranged leukemia. Together, our findings support development of an orally active covalent menin inhibitor as a new therapy for MLLr leukemia.

Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction.

Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.