Suite of Biochemical and Cell-Based Assays for the Characterization of Kirsten Rat Sarcoma (KRAS) Inhibitors and Degraders DOI Creative Commons

Medhanie Kidane,

Rene M. Hoffman,

Jennifer K. Wolfe-Demarco

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(12), P. 3921 - 3934

Published: Dec. 2, 2024

KRAS is an important oncogenic driver which mutated in numerous cancers. Recent advances the selective targeting of mutants via small molecule inhibitors and targeted protein degraders have generated increase research activity this area recent years. As such, there a need for new assay platforms to profile next generation improve on potency selectivity existing drug candidates, while evading emergence resistance. Here, we describe development panel biochemical cell-based assays evaluate binding function known chemical entities mutant KRAS. Our panels profiles quantitative interaction dissociation constants molecules against wild type, G12C, G12D, G12V KRAS, were congruent with published data. These can be leveraged additional interest beyond those described study, using both overexpressed cell-free systems endogenous levels.

Language: Английский

Targeted Covalent Modification Strategies for Drugging the Undruggable Targets DOI
Tomonori Tamura,

Masaharu Kawano,

Itaru Hamachi

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

The term "undruggable" refers to proteins or other biological targets that have been historically challenging target with conventional drugs therapeutic strategies because of their structural, functional, dynamic properties. Drugging such undruggable is essential develop new therapies for diseases where current treatment options are limited nonexistent. Thus, investigating methods achieve drugging an important challenge in medicinal chemistry. Among the numerous methodologies drug discovery, covalent modification has emerged as a transformative strategy. attachment diverse functional molecules provides powerful platform creating highly potent and chemical tools well ability provide valuable information on structures dynamics targets. In this review, we summarize recent examples biomolecules development therapeutics overcome discovery challenges highlight how contribute toward particular, focus use chemistry drugs, identification, screening, artificial modulation post-translational modifications, cancer specific chemotherapies, nucleic acid-based therapeutics.

Language: Английский

Citations

1
Targeting KRASG13C: Exploring Warhead Orientation with Cyclic Linker-Based Inhibitors DOI Creative Commons

Tonia Kirschner,

J. M. Rodríguez,

Emerson G. Moreira

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract The small GTPase KRAS is a key driver of carcinogenesis when mutated, and significant progress has been made in targeting KRASG12C other oncogenic variants. Building on our previous work demonstrating the potential nucleotide-based inhibitors with an acrylamide warhead to target KRASG13C, we designed synthesized library compounds cyclic linkers explore effect orientation reactivity toward Cys13. Using mass spectrometry, kinetic studies, protein X-ray crystallography, validated binding these modulators. In addition, computational predictions conformational space warheads provided insights into their reactivity, which agreed well experimental data. These findings advance understanding structure-reactivity relationship will be basis for further optimization.

Language: Английский

Citations

0
Targeting RAS and associated proteins DOI
Matthias Müller, Roger S. Goody, Daniel Rauh

et al.

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Discovery of Carbodiimide Warheads to Selectively and Covalently Target Aspartic Acid in KRASG12D DOI

Ludovica Stella Sirocchi,

Maximilian Scharnweber,

Sarah Oberndorfer

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Targeted covalent inhibitors are known to be successful therapeutics used in various indications. Covalent drugs typically target cysteine, as cysteine is well suited due its high nucleophilicity. However, low abundance protein binding sites represents a major limitation. As result, there need covalently additional nucleophilic amino acids. Recent literature has reported labeling aspartic acid KRASG12D. these compounds also bind KRASG12C, indicating their cross-reactivity along with acid. We report here carbodiimides novel reactive group selectively bearing carbodiimide moiety shown label KRASG12D biochemical and cellular assays. A high-resolution X-ray crystal structure was obtained, which illustrates the mechanism of bond formation Carbodiimide warheads show selectivity toward over other KRAS alleles represent new warhead suitable for context.

Language: Английский

Citations

0
Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display DOI

Mirai Kage,

Ryuji Hayashi, Atsushi Matsuo

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 110, P. 117830 - 117830

Published: July 6, 2024

Language: Английский

Citations

3
Innovative Therapeutic Approaches Targeting K-Ras: Analysis of Macrocyclic Compounds, Peptidomimetics, and Pyridopyrimidine Inhibitors DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(8), P. 1196 - 1198

Published: July 25, 2024

This Patent Highlight presents a detailed analysis of three novel classes compounds designed to inhibit multiple forms the K-Ras protein, as described in patent applications. These patents cover macrocyclic compounds, peptidomimetics, and pyridopyrimidine inhibitors. work explores each invention's design, mechanism action, relevance cancer treatment, results from assays demonstrating efficacy these compounds. The findings highlight significant potential inhibiting tumor growth inducing apoptosis cells, offering promising therapeutic options for K-Ras-driven cancers.

Language: Английский

Citations

1
Mutant KRAS inhibitors enter the scene of precision therapeutics for pancreatic cancer DOI Open Access
Gareth Pollin, Gwen Lomberk, Angela Mathison

et al.

Journal of Gastrointestinal Oncology, Journal Year: 2024, Volume and Issue: 15(4), P. 1996 - 2001

Published: Aug. 1, 2024

Language: Английский

Citations

0
Advancements in Targeted Therapeutics: Integrating Metabolic Modulation, Immune Engineering, and Biologic Formulation Technologies DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(9), P. 1430 - 1432

Published: Aug. 21, 2024

The rapid advancement of targeted therapeutics has significantly improved treatment precision and efficacy in oncology metabolic disorders. This article integrates key developments four areas: highly selective PPAR modulators for inflammatory diseases; CRISPR-engineered T-cell receptor therapies targeting the KRAS G12D mutation cancer; strategies to enhance antitumor immunity through glutamine metabolism modulation tumor microenvironment; a novel system analyzing coformulated biologics. These innovations highlight integration modulation, immune engineering, advanced biologic formulation, paving way more effective personalized therapeutic approaches.

Language: Английский

Citations

0
Advances in Cancer Treatment and Monitoring: Insights from KRAS Inhibitors and Germline Epitope Burden Monitoring DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(11), P. 1815 - 1817

Published: Oct. 15, 2024

This Patent Highlight explores recent cancer treatment and monitoring advancements, focusing on selective KRAS inhibitors targeting mutations like G12C G12D alongside germline epitope burden analysis. These innovations offer enhanced therapeutic precision personalized monitoring, improving the prediction of relapse tailoring strategies to individual patient profiles, significantly advancing field oncology.

Language: Английский

Citations

0
Suite of Biochemical and Cell-Based Assays for the Characterization of Kirsten Rat Sarcoma (KRAS) Inhibitors and Degraders DOI Creative Commons

Medhanie Kidane,

Rene M. Hoffman,

Jennifer K. Wolfe-Demarco

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(12), P. 3921 - 3934

Published: Dec. 2, 2024

KRAS is an important oncogenic driver which mutated in numerous cancers. Recent advances the selective targeting of mutants via small molecule inhibitors and targeted protein degraders have generated increase research activity this area recent years. As such, there a need for new assay platforms to profile next generation improve on potency selectivity existing drug candidates, while evading emergence resistance. Here, we describe development panel biochemical cell-based assays evaluate binding function known chemical entities mutant KRAS. Our panels profiles quantitative interaction dissociation constants molecules against wild type, G12C, G12D, G12V KRAS, were congruent with published data. These can be leveraged additional interest beyond those described study, using both overexpressed cell-free systems endogenous levels.

Language: Английский

Citations

0