Chemistry:Paluratide

Paluratide (development code LUNA18) was an investigational cyclic peptide KRAS inhibitor developed by Chugai Pharmaceutical, a member of the Roche Group, for the treatment of cancers with KRAS mutations. The compound was notable as an orally bioavailable macrocyclic peptide that could target intracellular protein-protein interactions, a class of targets traditionally considered "undruggable."

Development was discontinued in July 2025 due to a narrow therapeutic window compared to competing KRAS inhibitors.

Mechanism of action

Paluratide functions as a pan-RAS inhibitor, targeting multiple RAS isoforms including KRAS, NRAS, and HRAS. The compound binds with high affinity to KRAS^G12D, with a dissociation constant (K_d) of 0.043 nM, and blocks the interaction between KRAS^G12D and the guanine nucleotide exchange factor SOS1 with an IC₅₀ of less than 2.2 nM.

Unlike covalent KRAS inhibitors that target specific mutations (such as sotorasib for KRAS^G12C), paluratide was designed to inhibit RAS proteins through disruption of protein-protein interactions with guanine nucleotide exchange factors (GEFs). This mechanism allows the drug to affect RAS signalling regardless of the specific mutation, theoretically providing broader applicability across different KRAS-mutant cancers. The compound also demonstrates activity against downstream signalling pathways, affecting ERK and AKT phosphorylation.

Medical uses

Paluratide was being developed for the treatment of locally advanced or metastatic solid tumors harbouring RAS gene alterations. The drug demonstrated significant cellular activity against multiple cancer types with KRAS mutations in preclinical studies, including colorectal cancer, gastric cancer, non-small cell lung cancer, and pancreatic cancer.

Chemistry

Paluratide is an 11-member (11-mer) cyclic peptide with a molecular weight in the range of 1000–2000 g/mol, classified as a "middle-size" cyclic peptide. The compound features extensive N-alkylation, a modification that reduces hydrogen bond donors and improves oral absorption while maintaining cellular permeability. Its structure allows it to navigate the challenging boundary between small molecules and biologics, achieving properties of both classes. The compound demonstrated oral bioavailability ranging from 21% to 47% in preclinical animal studies without requiring special formulations.

Discovery

Paluratide was discovered through Chugai Pharmaceutical's cyclic peptide platform using an mRNA display library screening approach. The initial hit compound, designated AP8747, was identified from the mRNA display library and subsequently underwent extensive chemical optimization without scaffold hopping (maintaining the basic cyclic peptide structure). The optimization focused on increasing plasma stability, improving absorption, reducing clearance, and reducing hydrogen bond donors to achieve oral bioavailability.

The final clinical compound, LUNA18, emerged after modifications to four amino acid positions (positions 5, 7, 10, and 11) from an intermediate compound (compound 40). Key structure-activity relationship findings included: the side chain at position 5 preferring aromatic over aliphatic groups; physicochemical properties being adjustable at position 11; and biological activity enhancement through modifications at positions 7 and 10.

Chugai also developed a novel synthetic methodology that enabled the broadly applicable synthesis of highly N-alkylated cyclic peptide-like drugs. This method overcame three major technical challenges: formation of diketopiperazine, insufficient reactivity of amidation due to steric hindrance, and instability of cyclic peptides under acidic conditions. Using this approach, more than 4,000 cyclic peptides were synthesized with a process yield of 31% and final product purity of 97%.

Clinical trials

A Phase 1 dose-escalation and cohort expansion study (NCT05012618) was initiated in August 2021 to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of paluratide administered as a single agent or in combination with other anti-cancer drugs. The study, in the United States and Japan, was designed to enrol approximately 195 patients with locally advanced or metastatic solid tumors positive for documented RAS alterations.

Paluratide was administered orally as capsules. The study also evaluated combination therapy with cetuximab, an EGFR inhibitor.

Discontinuation

In July 2025, Chugai Pharmaceutical announced the discontinuation of paluratide along with four other early-stage clinical development projects (SAIL66, SOF10, STA551, and AMY109). The decision was made to dynamically and strategically allocate resources to priority projects to maximize the success rate of achieving the company's TOP I 2030 strategic goals. Chugai CEO Osamu Okuda stated on an earnings call in July 2025 that paluratide had a narrower therapeutic window than rival KRAS inhibitor products, leading the company to shift its focus to AUBE00, its second clinical-stage mid-size molecule KRAS inhibitor. Following Chugai's announcement, Roche removed paluratide from its clinical pipeline in October 2025 as part of its third-quarter results update.

See also

• KRAS
• Cyclic peptide
• Sotorasib – Covalent KRAS^G12C inhibitor
• Adagrasib – Covalent KRAS^G12C inhibitor
• Chugai Pharmaceutical
• Protein-protein interaction

External links

• Phase 1 Clinical Trial Information at ClinicalTrials.gov
• Development of LUNA18 at Journal of the American Chemical Society