Paluratide

{{Short description|Investigational KRAS inhibitor}} {{Multiple issues| {{Orphan|date=December 2025}} {{AI-generated|certain=yes|date=November 2025}} }} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=November 2025}} {{Infobox drug | drug_name = Paluratide | INN = | type =  | image = Paluratide.svg | image_class = skin-invert-image | width = 300px | alt = | caption = | image2 = | image_class2 =  | width2 = | alt2 = | caption2 = | imageL = | image_classL =  | widthL = | altL = | imageR = | image_classR =  | widthR = | altR = | captionLR =  | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA =  | licence_EU =  | DailyMedID =  | licence_US =  | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = Oral administration | class = | ATCvet = | ATC_prefix =  | ATC_suffix = | ATC_supplemental =  | legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US =  | legal_US_comment = | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status = Development discontinued | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =  | CAS_number = 2676177-63-0 | CAS_supplemental = | PubChem = 166509683 | PubChemSubstance = | IUPHAR_ligand = | DrugBank = | ChemSpiderID = 129321315 | UNII = AW3YP3CD9X | KEGG = | ChEBI = | ChEMBL = | NIAID_ChemDB = | PDB_ligand = | synonyms = LUNA18 | IUPAC_name = (3S,9S,12S,17S,20S,23S,27S,30S,36S)-20-[(2S)-butan-2-yl]-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-N,N,7,17,18,24,28,31-octamethyl-9-[(4-methylphenyl)methyl]-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,29,32,35-undecaoxospiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-27-carboxamide | chemical_formula = | C = 73 | H = 105 | N = 12 | O = 12 | F=5 | charge = | molecular_weight = | SMILES = CC[C@H](C)[C@H]1C(=O)N([C@H](C(=O)N2CC[C@H]2C(=O)N([C@H](C(=O)N(CC(=O)N[C@H](C(=O)N3CCC[C@H]3C(=O)NC4(CCCC4)C(=O)N([C@H](C(=O)N([C@@H](CC(=O)N([C@H](C(=O)N1)CC(C)C)C)C(=O)N(C)C)C)C5CCCC5)C)CCC6=CC(=C(C(=C6)F)C(F)(F)F)F)C)CC7=CC=C(C=C7)C)CC)C)C | Jmol = | StdInChI = 1S/C73H105F5N12O12/c1-15-44(6)60-69(100)84(11)45(7)64(95)90-35-31-53(90)68(99)88(16-2)56(39-46-27-25-43(5)26-28-46)67(98)83(10)41-57(91)79-51(30-29-47-37-49(74)59(50(75)38-47)73(76,77)78)65(96)89-34-21-24-52(89)63(94)81-72(32-19-20-33-72)71(102)87(14)61(48-22-17-18-23-48)70(101)86(13)55(66(97)82(8)9)40-58(92)85(12)54(36-42(3)4)62(93)80-60/h25-28,37-38,42,44-45,48,51-56,60-61H,15-24,29-36,39-41H2,1-14H3,(H,79,91)(H,80,93)(H,81,94)/t44-,45-,51-,52-,53-,54-,55-,56-,60-,61-/m0/s1 | StdInChI_comment = | StdInChIKey = ZQVKVYRBKAEFPD-DEBTURSASA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''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.<ref name="Tanada_2023">{{cite journal | vauthors = Tanada M, Tamiya M, Matsuo A, Chiyoda A, Takano K, Ito T, Irie M, Kotake T, Takeyama R, Kawada H, Hayashi R, Ishikawa S, Nomura K, Furuichi N, Morita Y, Kage M, Hashimoto S, Nii K, Sase H, Ohara K, Ohta A, Kuramoto S, Nishimura Y, Iikura H, Shiraishi T | title = Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor | journal = Journal of the American Chemical Society | volume = 145 | issue = 30 | pages = 16610–16620 | date = August 2023 | pmid = 37463267 | doi = 10.1021/jacs.3c03886 | bibcode = 2023JAChS.14516610T }}</ref> The compound was notable as an orally bioavailable macrocyclic peptide that could target intracellular protein-protein interactions, a class of targets traditionally considered "undruggable."<ref name="Ohta_2023">{{cite journal | vauthors = Ohta A, Tanada M, Shinohara S, Morita Y, Nakano K, Yamagishi Y, Takano R, Kariyuki S, Iida T, Matsuo A, Ozeki K, Emura T, Sakurai Y, Takano K, Higashida A, Kojima M, Muraoka T, Takeyama R, Kato T, Kimura K, Ogawa K, Ohara K, Tanaka S, Kikuchi Y, Hisada N, Hayashi R, Nishimura Y, Nomura K, Tachibana T, Irie M, Kawada H, Torizawa T, Murao N, Kotake T, Tanaka M, Ishikawa S, Miyake T, Tamiya M, Arai M, Chiyoda A, Akai S, Sase H, Kuramoto S, Ito T, Shiraishi T, Kojima T, Iikura H | title = Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets | journal = Journal of the American Chemical Society | volume = 145 | issue = 44 | pages = 24035–24051 | date = November 2023 | pmid = 37874670 | doi = 10.1021/jacs.3c07145 | bibcode = 2023JAChS.14524035O }}</ref>

Development was discontinued in July 2025 due to a narrow therapeutic window compared to competing KRAS inhibitors.<ref name="Fierce2025">{{cite web | vauthors = Taylor NP | title = Roche axes 4 Chugai solid tumor assets in early-phase clear-out | date = 24 October 2025 | url = https://www.fiercebiotech.com/biotech/roche-axes-4-chugai-solid-tumor-assets-early-phase-clearout | work = Fierce Biotech }}</ref>

== Mechanism of action == Paluratide functions as a pan-RAS inhibitor, targeting multiple RAS isoforms including KRAS, NRAS, and HRAS.<ref name="Tanada_2023" /> The compound binds with high affinity to KRASG12D, with a dissociation constant (Kd) of 0.043 nM, and blocks the interaction between KRASG12D and the guanine nucleotide exchange factor SOS1 with an IC50 of less than 2.2 nM.<ref name="MedChem">{{cite web | title = LUNA18 (Paluratide) - KRAS Inhibitor, ERK Inhibitor, RAS Inhibitor | url = https://www.medchemexpress.com/luna18.html | website = MedChemExpress }}</ref>

Unlike covalent KRAS inhibitors that target specific mutations (such as sotorasib for KRASG12C), paluratide was designed to inhibit RAS proteins through disruption of protein-protein interactions with guanine nucleotide exchange factors (GEFs).<ref name="Tanada_2023" /> 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.<ref name="MedChem" />

== Medical uses == Paluratide was being developed for the treatment of locally advanced or metastatic solid tumors harbouring RAS gene alterations.<ref name="NCT05012618">{{cite journal | title = A Dose-escalation Study of LUNA18 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion). | date = 29 July 2025 | url = https://clinicaltrials.gov/study/NCT05012618 | website = ClinicalTrials.gov | id = NCT05012618 }}</ref> 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.<ref name="Tanada_2023" />

== 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.<ref name="Tanada_2023" /> The compound features extensive N-alkylation, a modification that reduces hydrogen bond donors and improves oral absorption while maintaining cellular permeability.<ref name="Ohta_2023" /> 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.<ref name="Tanada_2023" />

== Discovery == Paluratide was discovered through Chugai Pharmaceutical's cyclic peptide platform using an mRNA display library screening approach.<ref name="Tanada_2023" /> 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).<ref name="Tanada_2023" /> 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.<ref name="Tanada_2023" />

Chugai also developed a novel synthetic methodology that enabled the broadly applicable synthesis of highly N-alkylated cyclic peptide-like drugs.<ref name="Nomura_2022">{{cite journal | vauthors = Nomura K, Hashimoto S, Takeyama R, Tamiya M, Kato T, Muraoka T, Kage M, Nii K, Kotake K, Iida S, Emura T, Tanada M, Iikura H | title = Broadly Applicable and Comprehensive Synthetic Method for ''N''-Alkyl-Rich Drug-like Cyclic Peptides | journal = Journal of Medicinal Chemistry | volume = 65 | issue = 19 | pages = 13401–13412 | date = October 2022 | pmid = 36109865 | doi = 10.1021/acs.jmedchem.2c01296 }}</ref> This method overcame three major technical challenges: formation of diketopiperazine, insufficient reactivity of amidation due to steric hindrance, and instability of cyclic{{failed verification|date=November 2025}} 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%.<ref name="Nomura_2022" />

== 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.<ref name="NCT05012618" /> 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.<ref name="NCT05012618" />

Paluratide was administered orally as capsules.<ref name="NCT05012618" /> The study also evaluated combination therapy with cetuximab, an EGFR inhibitor.<ref name="NCT05012618" />

== 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).<ref name=Chugai2025Q2>{{cite web |title=Conference on FY2025.12 Q2 Financial Results |date=24 July 2025 |url=https://www.chugai-pharm.co.jp/cont_file_dl.php?f=FILE_5_72.pdf&src=[%0],[%1]&rep=137,72}}</ref> 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.<ref name=Chugai2025Q2/>{{buzzword inline|date=November 2025}}

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.<ref name="Fierce2025" /> Following Chugai's announcement, Roche removed paluratide from its clinical pipeline in October 2025 as part of its third-quarter results update.<ref name="Fierce2025" />

== See also == *KRAS *Cyclic peptide *Sotorasib – Covalent KRASG12C inhibitor *Adagrasib – Covalent KRASG12C inhibitor *Chugai Pharmaceutical *Protein-protein interaction

== References == {{Reflist}}

== External links == *[https://clinicaltrials.gov/study/NCT05012618 Phase 1 Clinical Trial Information] at ClinicalTrials.gov *[https://pubs.acs.org/doi/10.1021/jacs.3c03886 Development of LUNA18] at Journal of the American Chemical Society

Category:Cyclic peptides Category:3-Fluorophenyl compounds Category:Trifluoromethyl compounds Category:Dimethylamino compounds