Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 139, P. 106720 - 106720
Published: July 13, 2023
Language: Английский
Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(4), P. 924 - 937
Published: Jan. 19, 2022
KRAS is the most frequently mutated oncogene, harboring mutations in approximately one seven cancers. Allele-specific KRASG12C inhibitors are currently changing treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive allele has fueled drug discovery efforts all mutants. Pan-KRAS drugs have potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, KRASG12A-mutant or wild-type-amplified cancers, as well cancers acquired resistance inhibitors. Here, we review actively pursued allele-specific pan-KRAS inhibition strategies their utility. Mutant-selective target fraction (approximately 13.6%) KRAS-driven A arsenal needed comprehensively conquer Conceptually, foresee two future classes medicines: mutant-selective targeting individual variant alleles therapeutics range alterations.
Language: Английский
Citations
196
Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)
Published: Dec. 20, 2022
Abstract Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets being studied, and most works focus on their enzymatic functions. Unlike small molecules, inhibit whole biological function binding to inducing subsequent proteasomal degradation. compensate for limitations transcription factors, nuclear proteins, other scaffolding difficult handle with traditional small-molecule inhibitors. have successfully degraded diverse such BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 ARV-471 exhibited excellent efficacy clinical II trials. However, what appropriate PROTAC achieve better benefits than inhibitors not fully understood. how rationally design an efficient optimize it be orally effective poses big challenges researchers. In this review, we summarize features technology, analyze detail general principles designing PROTACs, discuss typical application different categories. addition, also introduce progress relevant trial results representative assess may face. Collectively, our studies provide references further PROTACs.
Language: Английский
Citations
153
MedComm, Journal Year: 2023, Volume and Issue: 4(3)
Published: May 2, 2023
Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets
Language: Английский
Citations
117
Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)
Published: May 27, 2023
The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. most common form NCD is metabolic diseases, which affect people all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding the will generate novel targets for improved therapies across spectrum. Protein posttranslational modification (PTM) an important term that refers to biochemical specific amino acid residues in target proteins, immensely increases functional diversity proteome. range PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, several PTMs. Here, we offer review roles pathological consequences, including diabetes, obesity, fatty liver hyperlipidemia, atherosclerosis. Building upon this framework, afford description proteins pathways involved by focusing on PTM-based protein modifications, showcase pharmaceutical intervention preclinical studies clinical trials, future perspectives. Fundamental research defining mechanisms whereby regulate open new avenues therapeutic intervention.
Language: Английский
Citations
97
Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 740 - 757
Published: April 29, 2024
Language: Английский
Citations
91
Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(1), P. 167713 - 167713
Published: July 3, 2022
Language: Английский
Citations
82
Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(21), P. 8832 - 8876
Published: Jan. 1, 2022
ATTECs and several other emerging degrader technologies hijacking the lysosomal pathways greatly expand spectrum of degradable targets provide new opportunities for targeted drug discovery.
Language: Английский
Citations
76
Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(3), P. 1068 - 1102
Published: Jan. 1, 2023
This review summarizes chemical tools for cell engineering, introduces their wide application in diagnosis and therapy, discusses the challenges opportunities precision medicine.
Language: Английский
Citations
41
Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)
Published: Oct. 7, 2024
Abstract Colorectal cancer (CRC) remains one of the leading causes cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis CRC a testament to dysregulation these signaling cascades, which culminates in malignant transformation colonic epithelium. This review aims dissect foundational mechanisms implicated CRC, elucidate generalized principles underpinning neoplastic evolution progression. We discuss molecular hallmarks including genomic, epigenomic microbial features highlight role orchestration tumorigenic process. Concurrently, we advent targeted immune therapies assessing their impact on current clinical landscape. development has been informed deepening understanding oncogenic signaling, identification key nodes within can be exploited pharmacologically. Furthermore, explore potential integrating AI enhance precision therapeutic targeting patient stratification, emphasizing personalized medicine. In summary, our captures dynamic interplay between aberrant concerted efforts counteract changes through strategies, ultimately aiming pave way for improved prognosis treatment modalities colorectal cancer.
Language: Английский
Citations
39
Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 365, P. 1058 - 1073
Published: Jan. 1, 2024
Language: Английский
Citations
27