Selected Approaches to Disrupting Protein–Protein Interactions within the MAPK/RAS Pathway

Harwood, Stephen J.; Smith, Chris; Lawson, J. David; Ketcham, John M.

doi:10.3390/ijms24087373

Cited by 8 publications

(2 citation statements)

References 123 publications

(146 reference statements)

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“…These "switch" regions are dynamic allosteric binding pockets where RAS proteins switch between Peanlikhit et al 2024 an inactive state when bound to guanosine diphosphate (GDP) and an active state when bound to guanosine triphosphate (GTP) [82,83]. This process is facilitated by the binding of guanine nucleotide exchange factors (GEFs) such as Son of Sevenless (SOS1) to the Switch regions, which promote the dissociation of GDP and association of GTP, leading to oncogenic activation of mutated KRAS proteins [84]. Therefore, apigenin, flavonoids, or drugs that bind to these Switch regions would prevent the binding of GEFs to the Switch regions, preventing the oncogenic activation of mutated KRAS proteins.…”

Section: Discussionmentioning

confidence: 99%

In silico comparison of apigenin and related compounds with diverse pharmacological activities using AutoDock 4.2.6

Peanlikhit,

Aryal,

Welsh

et al. 2024

Preprint

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In recent years, molecular docking has been used to predict the binding affinity and interaction between flavonoids (ligands) and specific protein targets (receptors). However, existing studies have focused on a limited number of flavonoids with a small number of targeted proteins. In this study, on the other hand, we used the AutoDock 4.2.6 molecular docking software to compare the binding energy values and interactions of apigenin and 15 flavonoids with 24 different proteins known to be associated with oxidative stress, inflammation, carcinogenesis, and bacterial infections. This comparison will be important for the development of flavonoid-based drugs, allowing for the optimization of flavonoid drugs to better interact with their target proteins alone or in combination with conventional drugs. We used three-dimensional crystal structures of the receptors to identify the amino acids in the active site for docking purposes. Our goal was to identify potential inhibitors of these proteins and understand the structural configurations of flavonoids that affect their binding energy (binding affinity or inhibitory effects). We found that apigenin was a highly effective inhibitor for all tested proteins, with the highest binding energy of -8.21 kcal/mol with p38 mitogen-activated protein kinases and the lowest binding energy of -5.34 kcal/mol with cyclin-dependent kinase 4. In fact, apigenin and most of the tested flavonoids were better inhibitors for xanthine oxidase or DNA methyltransferase than known inhibitors. Our results also suggest that apigenin and selected flavonoids could be used to inhibit the oncogenic activity of KRAS mutations at codon 12 (i.e., G12C, G12D, and G12V) frequently found in solid tumors since they possess high binding energies with these mutated proteins. This finding offers an advantage over targeted therapy drugs that focus on specific KRAS mutations. Furthermore, most flavonoids have good safety profiles, so our resulting data are crucial for developing flavonoid-based drugs and present new insights into developing effective treatments that can attenuate the resistance and side effects of chemotherapy.

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Section: Discussionmentioning

confidence: 99%

In silico comparison of apigenin and related compounds with diverse pharmacological activities using AutoDock 4.2.6

Peanlikhit,

Aryal,

Welsh

et al. 2024

Preprint

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“…Recent studies also investigated other inhibitory molecules such as MRTX1133 and JAB-23000 that are selective inhibitors of KRAS G12D and KRAS G12V, respectively. A phase 1 trial testing RMC-6236, a triple inhibitor of KRAS (G12V, G12D, G13C, G13D, Q61H), NRAS (Q61X) and HRAS mutants, is also underway, with optimistic outcomes [ 84 , 85 ]. Nonetheless, the applicability of such molecules in the field of hematology has still been restricted due to various factors.…”

Section: Ras Targeting Therapeutic Strategiesmentioning

confidence: 99%

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Alawieh,

Cysique-Foinlan,

Willekens

et al. 2024

Blood Cancer J.

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NRAS and KRAS activating point mutations are present in 10–30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.

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Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance

Jiang,

Li,

Zhou

et al. 2024

Bioorganic & Medicinal Chemistry

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Selected Approaches to Disrupting Protein–Protein Interactions within the MAPK/RAS Pathway

Cited by 8 publications

References 123 publications

In silico comparison of apigenin and related compounds with diverse pharmacological activities using AutoDock 4.2.6

In silico comparison of apigenin and related compounds with diverse pharmacological activities using AutoDock 4.2.6

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance

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