Design, synthesis, and evaluation of purine and pyrimidine-based KRAS G12D inhibitors: Towards potential anticancer therapy DOI Creative Commons
S.L. Park, Venu Venkatarame Gowda Saralamma, Sagar D. Nale

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(7), P. e28495 - e28495

Published: April 1, 2024

Oncogenic RAS mutations, commonly observed in human tumors, affect approximately 30% of cancer cases and pose a significant challenge for effective treatment. Current strategies to inhibit the KRAS G12D mutation have shown limited success, emphasizing urgent need new therapeutic approaches. In this study, we developed several novel compounds by designing synthesizing purine pyrimidine analogs as inhibitors mutation. Our synthesized demonstrated potent anticancer activity against cell lines with mutation, effectively impeding their growth. They also exhibited low toxicity normal cells, indicating selective action cells carrying Notably, lead compound, PU1-1, induced programmed death G12D-mutated reduced levels active its downstream signaling proteins. Moreover, PU1-1 significantly shrunk tumor size pancreatic xenograft model further validating potential agent. These findings highlight purine-based candidates targeted therapy. However, exploration optimization these are essential meet unmet clinical needs KRAS-mutant cancers.

Language: Английский

Synthetic Approaches and Clinical Application of KRAS Inhibitors for Cancer Therapy DOI
M. Jiang, Shaowei Ma,

Ying Xuan

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 291, P. 117626 - 117626

Published: April 15, 2025

Language: Английский

Citations

0
Discovery of Novel SHP2 ATTEC Degraders against Pancreatic Ductal Adenocarcinoma Harboring KRAS(G12D) Mutations DOI
Yue Zhong, Yan Lü, Jiahui Li

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Aberrant expression of the phosphatase SHP2 is implicated in numerous cancers, including KRAS G12D mutation driven PDAC. Although several inhibitors have been reported, specific with potent efficacy are not yet available. Given elevated autophagy PDAC, herein, we first designed novel degraders through autophagosome-tethering compound strategy. Among them, preferred 11n formed hydrogen bonds Arg 111 and Glu 250 residues to enhance interactions between LC3. also possessed great selectivity against mutant cancer cells versus wild type. Moreover, degradation caused by manipulated signaling pathways associated cell apoptosis, metastasis, invasion inhibit tumor growth both vitro vivo. These findings only generated a useful tool for exploring potential targeting but offered promising candidates develop drugs based on mechanism.

Language: Английский

Citations

0
Small molecular inhibitors: Therapeutic strategies for pancreatic cancer DOI

Yuvasri Golivi,

Seema Kumari, Batoul Farran

et al.

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(7), P. 104053 - 104053

Published: June 6, 2024

Language: Английский

Citations

2
Beyond KRAS(G12C): Biochemical and Computational Characterization of Sotorasib and Adagrasib Binding Specificity and the Critical Role of H95 and Y96 DOI
Randa Mahran, Jonas N. Kapp, Salla Valtonen

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(10), P. 2152 - 2164

Published: Sept. 16, 2024

Mutated KRAS proteins are frequently expressed in some of the most lethal human cancers and thus have been a target intensive drug discovery efforts for decades. Lately, KRAS(G12C) switch-II pocket (SII-P)-targeting covalent small molecule inhibitors finally reached clinical practice. Sotorasib (AMG-510) was first FDA-approved inhibitor to treat KRAS(G12C)-positive nonsmall cell lung cancer (NSCLC), followed soon by adagrasib (MRTX849). Both drugs GDP-bound state KRAS(G12C), exploiting strong nucleophilicity acquired cysteine. Here, we evaluate similarities differences between sotorasib their RAS SII-P binding applying biochemical, cellular, computational methods. Exact knowledge engagement can enable targeting this site reversible mutants beyond G12C. We show that is strictly KRAS- but not KRAS(G12C)-specific due its unreplaceable interaction with H95. Unlike adagrasib, less dependent on H95 binding, making it isoform-agnostic compound, having similar functionality also NRAS HRAS G12C mutants. Our results emphasize accessibility oncogenic aid understanding molecular mechanism behind clinically observed resistance, associated especially secondary mutations Y96.

Language: Английский

Citations

2
Design, synthesis, and evaluation of purine and pyrimidine-based KRAS G12D inhibitors: Towards potential anticancer therapy DOI Creative Commons
S.L. Park, Venu Venkatarame Gowda Saralamma, Sagar D. Nale

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(7), P. e28495 - e28495

Published: April 1, 2024

Oncogenic RAS mutations, commonly observed in human tumors, affect approximately 30% of cancer cases and pose a significant challenge for effective treatment. Current strategies to inhibit the KRAS G12D mutation have shown limited success, emphasizing urgent need new therapeutic approaches. In this study, we developed several novel compounds by designing synthesizing purine pyrimidine analogs as inhibitors mutation. Our synthesized demonstrated potent anticancer activity against cell lines with mutation, effectively impeding their growth. They also exhibited low toxicity normal cells, indicating selective action cells carrying Notably, lead compound, PU1-1, induced programmed death G12D-mutated reduced levels active its downstream signaling proteins. Moreover, PU1-1 significantly shrunk tumor size pancreatic xenograft model further validating potential agent. These findings highlight purine-based candidates targeted therapy. However, exploration optimization these are essential meet unmet clinical needs KRAS-mutant cancers.

Language: Английский

Citations

2