A Phase 1 Open-label, Dose-escalation and Cohort Expansion Study of LUNA18 Monotherapy and Combination Therapy in Patients With Locally Advanced or Metastatic Solid Tumors

This is a Phase 1 dose-escalation and cohort expansion study that will evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of LUNA18 when administered as a single agent or in combination with other anti-cancer drugs in patients with locally advanced or metastatic solid tumors.

Start Date08 Oct 2021

Sponsor / Collaborator

Chugai Pharmaceutical Co., Ltd.

100 Clinical Results associated with Paluratide

100 Translational Medicine associated with Paluratide

100 Patents (Medical) associated with Paluratide

Literatures (Medical) associated with Paluratide

01 Aug 2024·Bioorganic & Medicinal Chemistry

Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display

Article

Author: Tanada, Mikimasa ; Sase, Hitoshi ; Irie, Machiko ; Furuichi, Noriyuki ; Kojima, Tetsuo ; Kawada, Hatsuo ; Hashimoto, Satoshi ; Ohara, Kazuhiro ; Shiraishi, Takuya ; Kuramoto, Shino ; Chiyoda, Aya ; Morita, Yuya ; Tamiya, Minoru ; Hayashi, Ryuji ; Ohta, Atsushi ; Ishikawa, Shiho ; Kage, Mirai ; Nishimura, Yoshikazu ; Nii, Keiji ; Ito, Toshiya ; Takano, Koji ; Takeyama, Ryuuichi ; Kotake, Tomoya ; Nomura, Kenichi ; Matsuo, Atsushi ; Iikura, Hitoshi

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.

08 Nov 2023·Journal of the American Chemical Society

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets

Article

Author: Kimura, Kaori ; Shiraishi, Takuya ; Nakano, Kazuhiko ; Tanaka, Masahiko ; Iida, Takeo ; Yamagishi, Yusuke ; Shinohara, Shojiro ; Hayashi, Ryuji ; Kariyuki, Shiori ; Ohta, Atsushi ; Sakurai, Yuuji ; Murao, Naoaki ; Nishimura, Yoshikazu ; Emura, Takashi ; Kojima, Tetsuo ; Ohara, Kazuhiro ; Irie, Machiko ; Sase, Hitoshi ; Higashida, Atsuko ; Kato, Tatsuya ; Kuramoto, Shino ; Hisada, Nozomi ; Tamiya, Minoru ; Takano, Ryusuke ; Akai, Sho ; Tanaka, Shota ; Kawada, Hatsuo ; Ito, Toshiya ; Morita, Yuya ; Kojima, Miki ; Nomura, Kenichi ; Muraoka, Terushige ; Iikura, Hitoshi ; Ishikawa, Shiho ; Ozeki, Kazuhisa ; Tachibana, Tatsuhiko ; Torizawa, Takuya ; Takeyama, Ryuuichi ; Kikuchi, Yasufumi ; Chiyoda, Aya ; Ogawa, Kotaro ; Miyake, Taiji ; Takano, Koji ; Kotake, Tomoya ; Tanada, Mikimasa ; Arai, Masako ; Matsuo, Atsushi

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

02 Aug 2023·Journal of the American Chemical Society

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Article

Author: Kawada, Hatsuo ; Takeyama, Ryuuichi ; Irie, Machiko ; Hayashi, Ryuji ; Ohara, Kazuhiro ; Nomura, Kenichi ; Hashimoto, Satoshi ; Nishimura, Yoshikazu ; Takano, Koji ; Kotake, Tomoya ; Tamiya, Minoru ; Furuichi, Noriyuki ; Nii, Keiji ; Chiyoda, Aya ; Shiraishi, Takuya ; Ishikawa, Shiho ; Sase, Hitoshi ; Morita, Yuya ; Tanada, Mikimasa ; Ohta, Atsushi ; Ito, Toshiya ; Matsuo, Atsushi ; Kage, Mirai ; Iikura, Hitoshi ; Kuramoto, Shino

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10^-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.

100 Deals associated with Paluratide

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	JP	Chugai Pharmaceutical Co., Ltd.	08 Oct 2021
Solid tumor	Phase 1	US	Chugai Pharmaceutical Co., Ltd.	08 Oct 2021

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