2. Academic Validation
  3. A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer

  • bioRxiv. 2024 Jan 24:2023.05.17.541233. doi: 10.1101/2023.05.17.541233.
Jeremy B Foote,  Tyler E Mattox,  Adam B Keeton,  Xi Chen,  Forrest T Smith,  Kristy L Berry,  Thomas Holmes,  Junwei Wang,  Chung-Hui Huang,  Antonio B Ward,  Cherlene Hardy,  Karrianne G Fleten,  Kjersti Flatmark,  Karina J Yoon,  Sujith Sarvesh,  Puranchandra Nagaraju Ganji,  Yulia Maxuitenko,  Jacob Valiyaveettil,  Julienne L Carstens,  Donald J Buchsbaum,  Jennifer Yang,  Gang Zhou,  Elmar Nurmemmedov,  Ivan Babic,  Vadim Gaponenko,  Hazem Abdelkarim,  Amit K Mitra,  Michael R Boyd,  Upender Manne,  Sejong Bae,  Bassel F El-Rayes,  Gary A Piazza
PMID: 38328254 DOI: 10.1101/2023.05.17.541233
Abstract

Here we characterize a novel pan-RAS inhibitor, ADT-007, that potently and selectively inhibited the growth of histologically diverse Cancer cell lines with mutant or activated Ras irrespective of the Ras mutation or isozyme. Growth inhibition was dependent on activated Ras and associated with reduced GTP-RAS levels and MAPK/Akt signaling. ADT-007 bound Ras in lysates from sensitive cells with sub-nanomolar EC 50 values but did not bind Ras in lysates from insensitive cells with low activated Ras. Insensitivity to ADT-007 was attributed to metabolic deactivation by UGT-mediated glucuronidation, providing a detoxification mechanism to protect normal cells from pan-RAS inhibition. Molecular modeling and experiments using recombinant Ras revealed that ADT-007 binds Ras in a nucleotide-free conformation to block GTP activation. Local injection of ADT-007 strongly inhibited tumor growth in syngeneic immune competent and xenogeneic immune deficient mouse models of colorectal and pancreatic Cancer and activated innate and adaptive immunity in the tumor microenvironment.

Significance: ADT-007 is a novel pan-RAS inhibitor with a unique mechanism of action having potential to circumvent resistance to mutant-specific KRAS inhibitors and activate antitumor immunity. The findings support further development of ADT-007 analogs and/or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy for Ras mutant cancers.

Background: It is projected that colorectal Cancer (CRC) and pancreatic ductal adenocarcinoma (PDA) will cause 52,580 and 49,830 deaths in the US in 2023, respectively (1). The 5-year survival rates for CRC and PDA are 65% and 12%, respectively (1). Over 50% of CRC and 90% of PDA patients harbor mutations in KRAS genes that are associated with poor prognosis, making the development of novel KRAS inhibitors an urgent unmet medical need (2).

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157887
    99.06%, RAS抑制剂
    Ras
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