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Small Molecule KRAS Inhibitors With Potent Antitumor Activity

Many different types of oral medication.
Credit: Steve Buissinne/ Pixabay
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The mitogen-activated protein kinases (MAPK) pathway regulates cellular growth, proliferation, differentiation and survival. The H-Ras, K-Ras and N-Ras proteins involved in this pathway are frequently mutated in human cancers. Mutation of the Ras gene causes signaling dysregulation, which can promote tumor development and growth. KRAS mutations, especially G12D, G12V and G12C, are highly prevalent in pancreatic, colorectal and lung cancers.

Quanta Therapeutics, a biopharmaceutical company producing targeted therapies to treat Ras-driven cancers, announced data on two chemically distinct allosteric, oral small molecule KRAS inhibitors with potent anti-tumor activity at the American Association for Cancer Research (AACR) 2023 Annual Meeting. Technology Networks spoke to Dr. Cameron Pitt, chief business officer at Quanta, to learn more about KRAS as a target for cancer therapeutics, avoiding known resistance mechanisms and the effectiveness of both novel inhibitors.

Kate Robinson (KR): Why is KRAS an important target for cancer therapeutics?

Cameron Pitt (CP): Nearly 25% of all cancers are caused by Ras mutations, and KRAS mutations are found primarily in colorectal, pancreatic and lung cancers, so this is a significant unmet need. Recently approved treatments in this space show the potential impact of KRAS inhibitors but they only target one mutation, G12C, which represents roughly 10% of KRAS-driven cancers, and resistance can develop, so we need treatments that provide durable efficacy without adding toxicity.

KR: What is allosteric modulation? Why is it important in drug discovery?

CP: Allosteric modulation is having the ability to modulate protein function without directly blocking an active site – this is critical for oncogenic drivers that depend on protein–protein interactions rather than enzymatic activity. KRAS mutations are hard to target and have previously been deemed “undruggable” because they drive a conformation of the protein that does not provide an obvious pocket in which a drug can bind to inhibit cancer signaling. Allosteric mechanisms are key to unlocking the potential to treat these previously undruggable mutations. Quanta’s proprietary discovery tool, Second Harmonic Generation (SHG), measures subtle changes in protein binding, allowing the team to design allosteric inhibitors with activity against mutations beyond G12C (including G12D, G12V).

KR: Can you talk us through the mechanisms of both QTX3034 and QTX3046?

CP: QTX3034 and QTX3046 are based on different scaffolds with varied physiochemical properties. QTX3034 is a multi-KRAS inhibitor with activity across several variants including G12D, G12V and wildtype KRAS, while sparing NRAS and HRAS, which is critical for safety in normal cells. QTX3046 is selective for G12D and has potent allosteric effects across multiple conformations of the protein, including its active state. QTX3034 and QTX3046 tightly bind to GDP-bound G12D-mutated KRAS and inhibit GDP-to-GTP nucleotide exchange, which prevents KRAS activation and subsequent RAF binding. QTX3046 also potently binds to GTP-bound KRAS and directly inhibits KRAS-RAF1 protein–protein interaction. QTX3034 and QTX3046 treatment potently and durably inhibits cellular MAPK signaling for anti-tumor activity.

KR: You recently shared data about both molecules at AACR 2023. Can you tell us more about the data presented and its significance?

CP: We presented preclinical data on two distinct development candidates targeting mutant KRAS: QTX3034, a multi-KRAS inhibitor and QTX3046, a G12D-selective inhibitor. Both molecules have best-in-class potential among oral inhibitors of KRAS G12D. Data demonstrate that oral administration of QTX3034 and QTX3046 treatment achieved tumor regression in KRAS G12D tumor mouse xenograft models. Data also show positive preclinical profiles with attractive drug-like properties for oral dosing and safety across species. Additionally, both candidates display CNS-penetrance, which is highly important to address brain metastases common in solid tumor indications where KRAS mutations are most prevalent.

KR: How can the majority of KRAS mutations be targeted while evading known resistance mechanisms?

CP: Recently approved medicines have shown clinical benefit against the G12C mutation, but G12C only represents a small subset of KRAS-driven cancer. Selectively targeting G12D and other mutant forms significantly expands the number of patients and tumor types that can potentially be addressed by KRAS inhibitors. Using a direct small molecule with allosteric activity across multiple conformations of oncogenic KRAS proteins for modulation of downstream signaling may diminish the potential for various upstream mechanisms of reactivation and resistance that have been observed with the clinical G12C inhibitors.

Our data and that of others support combination with inhibitors of growth factor signaling (i.e., EGFR inhibitors) for durable efficacy, and Quanta’s direct oral small molecules have attractive physiochemical properties facilitating combination use. We presented data at AACR 2023 showing synergy for both QTX3034 and QTX3046 with EGFR modulators.

KR: How has the identification of allosteric modulators of membrane-bound protein assisted in the drug development process?

CP: SHG is Quanta’s high throughput discovery platform capturing allosteric modulation of any target, including membrane protein complexes. The assays leverage proprietary optical technology capable of measuring conformational changes in proteins and multi-subunit complexes, enabling the discovery of allosteric small molecules with novel chemical scaffolds. We then use additional tools, including structure-based medicinal chemistry approaches, to optimize compounds for potency and oral bioavailability.

Dr. Cameron Pitt was speaking to Kate Robinson, Assistant Editor for Technology Networks.