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Ref Type abstract
PMID
Authors Meagan B Ryan; Chun Li; Yongxin Han; Klaus P Hoeflich; Michael R Hale; Margit Hagel
Title Abstract A089: NST-628 is a potent, fully brain-penetrant, RAS/MAPK pathway molecular glue inhibitor with efficacy in CNS tumor models
Journal Vol Issue Date Pages Journal Short Title
22 12_supplement 2023 Mol Cancer Ther
URL https://aacrjournals.org/mct/article/22/12_Supplement/A089/730457
Abstract Text Alterations in the RAS/RAF/MEK/ERK signaling cascade are common across multiple solid tumor types and aberrant signaling of the pathway is a driver for RAS- and RAF-driven cancers. Apart from approved mutation selective inhibitors for BRAF Class I and KRAS G12C mutations, other mutations of RAS and RAF are not directly addressable by currently approved inhibitors and there is a need for inhibitors with superior efficacy, durability and tolerability for the MAPK pathway in RAS- and RAF-driven cancers. Currently approved inhibitors of the RAS-MAPK pathway also have limited central nervous system (CNS) exposure and an area of significant unmet patient need exists for patients with primary and metastatic tumors harboring RAS-MAPK pathway alterations. NST-628 has CNS permeability, with a Kpu,u >1, that is far higher than trametinib or VS-6766 (Kpu,u of 0.11 and 0.18 respectively). The predicted effective human half-life of NST-628 (~9h) is amenable to daily dosing in the clinic. In vivo, NST-628 leads to a dose-dependent inhibition of the MAPK pathway in murine brain tissue[KS1] as measured by phospho-ERK. In an intracranial luciferase-tagged SK-MEL-2 xenograft model (NRAS Q61R), NST-628 leads to tumor regressions with a daily dosing regimen (3 mg/kg QD). Tumor regressions as measured by bioluminescent imaging (BLI) were only seen with NST-628 (50%) in the SK-MEL-2 model, whereas trametinib and VS-6766 showed minimal efficacy due to low exposure in the CNS. In the NF-1 mutant MeWo (NF1 Q1336*) melanoma intracranial xenograft model (luciferase tagged), NST-628 led to tumor regressions at two dosing regimens (1, 3 mg/kg QD) and tumor stasis at lower doses (0.3 mg/kg) as measured by BLI. In contrast, the brain penetrant type II RAF inhibitor DAY101 (formerly TAK580) showed no efficacy in the MeWo model and resulted in paradoxical pathway hyper-activation, as determined by enhanced PD response and tumor growth. Only NST-628 effectively inhibited MAPK signaling as measured by DUSP6 transcript in a time- and dose-dependent manner. Overall, survival of mice harboring MeWo intracranial tumors was also significantly increased versus vehicle control and DAY101 treatment groups. These data collectively support best-in-class potential of NST-628 and initiation of clinical trials in patients with solid tumors harboring RAS- and RAF-mutations, including those presenting clinically with brain metastases and primary intracranial tumors.

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