- Data highlight favorable preclinical profiles for two chemically-distinct allosteric, oral small molecule KRAS inhibitors with potent anti-tumor activity -
ORLANDO, Fla., April 14, 2023 (GLOBE NEWSWIRE) -- Quanta Therapeutics, a privately-held biopharmaceutical company pioneering targeted therapies to treat RAS-driven cancers, announced data from two late-breaking presentations at the American Association for Cancer Research (AACR) Annual Meeting being held April 14-19, 2023, in Orlando, Florida. QTX3034, a multi-KRAS inhibitor, and QTX3046, a G12D-selective KRAS inhibitor, demonstrate favorable preclinical profiles, including potent anti-tumor activity with oral bioavailability and brain penetration, supporting the initiation of IND-enabling studies and clinical development for KRAS-driven solid tumor indications. Leveraging unique chemistry that targets multiple conformations of KRAS, Quanta Therapeutics' allosteric approach has the potential to expand the scope of treatable KRAS-mutant cancers while evading known mechanisms of KRAS-mediated resistance.
“KRAS G12C inhibitors were a breakthrough for the treatment of cancer patients, but they only address around 10% of KRAS-driven tumors and the duration of clinical benefit is limited. Quanta’s multi-KRAS and G12D-selective inhibitors address a larger portion of the KRAS-mutated patient population. By disrupting the active RAS signaling complex, we have two potentially best-in-class oral, CNS-penetrant small molecules that can lead the next wave of innovation in KRAS-driven cancer treatment,” said Perry Nisen, MD, PhD, Chief Executive Officer of Quanta Therapeutics. “Our proprietary discovery tools and unique medicinal chemistry enabled the development of these programs, and we’re excited to present the data that supported advancement into IND-enabling studies with the goal of initiating clinical trials in 2024.”
Data from the presentations are described below.
QTX3034, a potent, selective, and orally bioavailable allosteric multi-KRAS inhibitor:
- Demonstrated binding affinity to GDP-bound KRAS G12D/V mutant and wild-type proteins; binding prevents GTP exchange and locks KRAS in the GDP-bound inactive state, thereby disrupting the KRAS: RAF1 effector interaction
- Exhibited potent, durable, and dose-responsive inhibition of MAPK/KRAS signaling in cells expressing human KRAS variants
- Exhibited robust anti-proliferative activity against mutant KRAS-driven cancer cells
- Shows synergy with EGFR modulators in a panel of KRASG12D cancer cell lines
- Demonstrated robust, single-agent anti-tumor activity in preclinical colorectal, pancreatic, and lung cancer xenograft models after oral administration
- Demonstrated a favorable pharmacokinetic and initial safety profile, including good oral bioavailability and brain penetration, across several key parameters
- Preclinical data support the advancement of QTX3034 into IND-enabling studies for clinical investigation in mutant KRAS-driven solid tumors
QTX3046, a potent, selective, and orally bioavailable non-covalent KRASG12D inhibitor:
- Selectively binds to KRAS-G12D, preventing GTP exchange and allosterically blocking the active conformation, thereby disrupting the KRASG12D: RAF1 effector interaction in biochemical and cell-based assays
- Exhibited potent, durable, and dose-responsive inhibition of KRASG12D-mediated MAPK signaling and induced apoptotic markers
- Demonstrated selective inhibition of KRASG12D-driven cell signaling and proliferation in isogenic cell panels
- Displays synergy with EGFR modulators in a panel of KRASG12D cancer cell lines
- Demonstrated robust, single-agent anti-tumor activity in preclinical colorectal, pancreatic, and lung cancer xenograft models after oral administration
- Demonstrated a favorable pharmacokinetic and initial safety profile, including good oral bioavailability and brain penetration
- Preclinical data support the advancement of QTX3046 into IND-enabling studies for clinical investigation in KRASG12D-driven solid tumor indications
Poster presentation details are as follows:
Title: Discovery and characterization of QTX3034, a potent, selective, and orally bioavailable allosteric KRAS inhibitor
Date and Time: Wednesday April 19, 2023 9:00 AM - 12:30 PM
Session Name: Late-Breaking Research: Experimental and Molecular Therapeutics 3
Abstract Number: LB320
Title: Discovery and characterization of QTX3046, a potent, selective, and orally bioavailable non-covalent KRAS G12D inhibitor
Date and Time: Wednesday April 19, 2023 9:00 AM - 12:30 PM
Session Name: Late-Breaking Research: Experimental and Molecular Therapeutics 3
Abstract Number: LB321
About RAS and the MAPK Pathway
The mitogen-activated protein kinase (MAPK) pathway is a chain of proteins that includes the signaling molecules RAS, RAF, MEK, and ERK. It is a central pathway that regulates cellular growth, proliferation, differentiation, and survival. When one of the proteins is mutated, it can drive tumor development and growth. RAS is the most frequently mutated oncogene in cancer, with KRAS mutations occurring in nearly one-quarter of all human cancers. RAS mutations impair the ability of RAS to convert from its active GTP-bound “ON” form into its inactive GDP-bound “OFF” state, leading to the sustained activation of the MAPK signaling pathway and ultimately driving tumorigenesis. KRAS mutations, especially G12D, G12V, and G12C, are highly prevalent in pancreatic, colorectal, and lung cancers. First-generation KRAS inhibitors have demonstrated clinical benefit, but their impact is limited to a subset of patients with a single type of KRAS mutation (G12C), and these tumors commonly develop resistance to treatment.
About Quanta Therapeutics
Quanta Therapeutics is a private biopharmaceutical company focused on the most prevalent and elusive target in oncology—RAS. Our vision is to develop novel small molecule cancer medicines by selectively targeting protein-protein interactions that are key to oncogenic RAS activity. Driving Quanta's success is our unique high-throughput platform that applies Second Harmonic Generation (SHG) optical technology to identify allosteric modulators of membrane-bound protein complexes. The Quanta team has extensive drug development expertise and substantial research experience in the RAS space. By applying innovative medicinal chemistry and its unique protein conformation detection technology, Quanta aims to advance differentiated, next-generation RAS programs that address the resistance paradigms of targeted therapy in oncology.
Find more information at https://www.quantatx.com/
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Quanta Therapeutics
Heather Meeks
661-992-6907
heather.meeks@quantatx.com
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