Abstract 475: Preclinical development of ABM-168, a novel MEK Inhibitor to treat cancer with brain tumors

Abstract

The Mitogen-Activated Extracellular Signal-Regulated Kinase (MEK) is a critical member of the MAPK signaling pathway family. In cancer cells, the abnormality in MAPK pathway associates with the mutation occurred in the upstream KARS or BRAF. Blockage of the pathway with MEK1/2 inhibitors result in inhibiting cell proliferation and inducing apoptosis. It hence has the potential for clinical benefits for treating cancers with RAS/RAF dysfunctions.ABM-168 is a novel small molecule, allosteric, highly selective MEK inhibitor with high water solubility, cell permeability and brain penetration. We have demonstrated its anti-cancer efficacy in vitro in multiple cancer cell lines, and in vivo in several xenograft, subcutaneous, intracardiac and intracranial, animal models. In-vitro data showed the similar on-target enzyme activity of ABM-168 to marketed MEK inhibitors, as well as high anti-proliferation activities (IC50 <30nM) in multiple cancer cell lines with BRAF or RAS or NF1 mutation like A375, Colo-829, HT-29, MiaPaca-2, LN-229 etc. In vivo pharmacology studies demonstrated that ABM-168 had good potencies of tumor growth inhibitions with oral dose alone or combo with other drugs or compounds in multiple xenograft cancer models: In an A375-luc intracardiac melanoma metastatic model, ABM-168 at 2 mg/kg PO BID demonstrated an antitumor activity comparable to ABM-1310 (A highly BBB-permeable BRAF inhibitor developed by ABM Therapeutics) at different dose levels and frequencies. On Day 28, the BLI% decreased 95.5%, 93.2%, 99.44% and 99.7% for ABM-168 (2 mg/kg), ABM-1310 at 1 mg/kg PO QD, 5 mg/kg PO QD and 2.5 mg/kg PO BID, respectively. In a LN229 glioblastoma orthotopic model in BALB/c nude mice, ABM-168 at 5-10 mg/kg PO QD showed a significant activity, the BLI (%) decreased in the brain 68 % on Day 49. These results indicate that the BBB-permeable ABM-168 may be efficacious as a single agent or combo with ABM-1310 to treat BRAF-mutant, advanced cancers with or without brain metastases or primary CNS tumors with an abnormal up-regulated MAPK signal. Non-clinical pharmacokinetics studies also showed that ABM-168 had a favorable ADME profile both in vitro and in vivo, and good brain penetration in animals. Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs were all completed. Based on these supportive preclinical study results, the IND of ABM-168 was submitted in 2022 Q3 to investigate its safety in human, which will be followed by further clinic development as a single agent, or in combination with other molecules to treat advanced cancers resulted from the abnormal MAPK signal pathway, particularly with brain tumors.

Citation Format: Chen Chen, Charles Huang, Min Xu, YouQin Chen, Lanjiao Zhao, Yang Chen, Yong Hu. Preclinical development of ABM-168, a novel MEK Inhibitor to treat cancer with brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 475.