Pinpointing Acidic Residues in Proteins DOI
Weimin Xuan, Jun‐An Ma

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(5)

Published: Feb. 2, 2024

Abstract It is of great importance to pinpoint specific residues or sites a protein in biological contexts enable desired mechanism action for small molecules precisely control function. In this regard, acidic including aspartic acid (Asp) and glutamic (Glu) hold potential due their prevalence unique To unlock the largely untapped potential, efforts have been made recently by synthetic chemists, chemical biologists pharmacologists. Herein, we would like highlight remarkable progress particularly introduce electrophiles that exhibit reactivity carboxylic acids, light‐induced reactivities acids genetically encoded noncanonical amino allow manipulations at residues. We also comment on certain unresolved challenges, hoping draw more attention rapidly developing area.

Language: Английский

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update DOI

Laura Hillebrand,

Xiaojun Julia Liang,

Ricardo A. M. Serafim

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758

Published: May 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Language: Английский

Citations

49
Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D DOI Creative Commons
Qinheng Zheng, Ziyang Zhang, Keelan Z. Guiley

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(9), P. 1114 - 1122

Published: March 5, 2024

K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine K-Ras-G12C mutation lock it a signaling-incompetent state. However, covalent inhibition of G12D, frequent particularly prevalent pancreatic ductal adenocarcinoma, has remained elusive due to lack aspartate-targeting chemistry. Here we present set malolactone-based electrophiles that exploit ring strain crosslink K-Ras-G12D at mutant aspartate form stable complexes. Structural insights from X-ray crystallography exploitation stereoelectronic requirements for attack electrophile allowed development substituted malolactone resisted by aqueous buffer but rapidly crosslinked with aspartate-12 both GDP GTP GTP-state targeting effective suppression downstream signaling, selective K-Ras-G12D-driven proliferation vitro xenograft growth mice.

Language: Английский

Citations

34
Development of covalent inhibitors: Principle, design, and application in cancer DOI Creative Commons
Lang Zheng, Yang Li,

Defa Wu

et al.

MedComm – Oncology, Journal Year: 2023, Volume and Issue: 2(4)

Published: Oct. 31, 2023

Abstract Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages cancer therapy. As opposed noncovalent inhibitory drugs, covalent reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming selectively recognize bind protein targets addressing some of the challenges faced by drugs. Most successful targeted depend primarily binding‐site cysteine residues, but this has limitations for certain that lack targetable residues. Recently, rational design probes targeting other such as lysine, tyrosine, serine, turned out be another promising strategy Thus, development novel strategies extend scope binding improve properties is required. This review gives summary noncysteine from different aspects, including target identification, structure–activity relationships, strategies, properties, hope providing scientific reference future means expanding research

Language: Английский

Citations

26
Targeting KRAS Diversity: Covalent Modulation of G12X and Beyond in Cancer Therapy DOI

Tonia Kirschner,

Matthias Müller, Daniel Rauh

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6044 - 6051

Published: April 15, 2024

The GTPase KRAS acts as a switch in cellular signaling, transitioning between inactive GDP-bound and active GTP-bound states. In about 20% of human cancers, oncogenic RAS mutations disrupt this balance, favoring the form promoting proliferative thus rendering an appealing target for precision medicine oncology. 2013, Shokat co-workers achieved groundbreaking feat by covalently targeting previously undiscovered allosteric pocket (switch II (SWIIP))

Language: Английский

Citations

10
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
The expanding repertoire of covalent warheads for drug discovery DOI
Namrashee V. Mehta, Mariam S. Degani

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103799 - 103799

Published: Oct. 13, 2023

Language: Английский

Citations

21
Pathways and mechanism of MRTX1133 binding to KRAS G12D elucidated by molecular dynamics simulations and Markov state models DOI

Gao Tu,

Yaguo Gong,

Xiaojun Yao

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 274, P. 133374 - 133374

Published: June 24, 2024

Language: Английский

Citations

7
Inhibition of GTPase KRAS G12D : a review of patent literature DOI
Yuhang Li, Le Yang, Xiaoran Li

et al.

Expert Opinion on Therapeutic Patents, Journal Year: 2024, Volume and Issue: 34(8), P. 701 - 721

Published: June 17, 2024

KRAS is a critical oncogenic protein intricately involved in tumor progression, and the difficulty targeting has led it to be classified as an 'undruggable target.' Among various mutations,

Language: Английский

Citations

4
Proteome-wide Ligand and Target Discovery by Using Strain-Enabled Cyclopropane Electrophiles DOI
Yue Liu, Zhongtang Yu, Peishan Li

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(30), P. 20823 - 20836

Published: July 17, 2024

The evolving use of covalent ligands as chemical probes and therapeutic agents could greatly benefit from an expanded array cysteine-reactive electrophiles for efficient versatile proteome profiling. Herein, to expand the current repertoire electrophiles, we developed a new class strain-enabled based on cyclopropanes. Proteome profiling has unveiled that C163 lactate dehydrogenase A (LDHA) C88 adhesion regulating molecule 1 (ADRM1) are ligandable residues modulate protein functions. Moreover, fragment-based ligand discovery (FBLD) revealed one fragment (

Language: Английский

Citations

4
Peptide and Protein Cysteine Modification Enabled by Hydrosulfuration of Ynamide DOI Creative Commons
Changliu Wang, Zhenguang Zhao,

Reem Ghadir

et al.

ACS Central Science, Journal Year: 2024, Volume and Issue: 10(9), P. 1742 - 1754

Published: Aug. 21, 2024

Efficient functionalization of peptides and proteins has widespread applications in chemical biology drug discovery. However, the chemoselective site-selective modification remains a daunting task. Herein, highly efficient chemo-, regio-, stereoselective hydrosulfuration ynamide was identified as an method for precise by uniquely targeting thiol group cysteine (Cys) residues. This novel could be facilely operated aqueous buffer fully compatible with wide range proteins, including small model large full-length antibodies, without compromising their integrity functions. Importantly, this reaction provides Z-isomer corresponding conjugates exclusively superior stability, offering approach to peptide protein therapeutics. The potential application further exemplified Cys-bioconjugation variety ynamide-bearing functional molecules such molecule drugs, fluorescent/affinity tags, PEG polymers. It also proved redox proteomic analysis through Cys-alkenylation. Overall, study bioorthogonal tool Cys-specific functionalization, which will find broad synthesis peptide/protein conjugates.

Language: Английский

Citations

4