Insights into pralsetinib resistance to the non-gatekeeper RET kinase G810C mutation through molecular dynamics simulations

Cao, Shu; Changbin, Tan; Fei, Anhua; Gangqiang, HU; Fu, Ming; Lee, Jun

doi:10.1007/s00894-022-05429-9

Cited by 6 publications

(3 citation statements)

References 63 publications

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“…ADMET prediction is a fundamental criterion for assessing drug-likeness properties. We used two online prediction tools, SwissADME (http://www.swissadme.ch/, accessed on 10 June 2023) [34] and ADMETlab 2.0 (https://admetmesh.scbdd.com/, accessed on 10 June 2023) [36], to predict the ADMET characteristics of the generated molecules.…”

Section: Admet Predictionmentioning

confidence: 99%

Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder–Decoder Model

Liu,

Zhao,

Huang

2024

IJMS

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The receptor tyrosine kinase RET (rearranged during transfection) plays a vital role in various cell signaling pathways and is a critical factor in the development of the nervous system. Abnormal activation of the RET kinase can lead to several cancers, including thyroid cancer and non-small-cell lung cancer. However, most RET kinase inhibitors are multi-kinase inhibitors. Therefore, the development of an effective RET-specific inhibitor continues to present a significant challenge. To address this issue, we built a molecular generation model based on fragment-based drug design (FBDD) and a long short-term memory (LSTM) encoder–decoder structure to generate receptor-specific molecules with novel scaffolds. Remarkably, our model was trained with a molecular assembly accuracy of 98.4%. Leveraging the pre-trained model, we rapidly generated a RET-specific-candidate active-molecule library by transfer learning. Virtual screening based on our molecular generation model was performed, combined with molecular dynamics simulation and binding energy calculation, to discover specific RET inhibitors, and five novel molecules were selected. Further analyses indicated that two of these molecules have good binding affinities and synthesizability, exhibiting high selectivity. Overall, this investigation demonstrates the capacity of our model to generate novel receptor-specific molecules and provides a rapid method to discover potential drugs.

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Section: Admet Predictionmentioning

confidence: 99%

Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder–Decoder Model

Liu,

Zhao,

Huang

2024

IJMS

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“…On-target RET solvent front mutations involving the G810 residue (G810 C/S/R) represent a recurrent mechanism of resistance, leading to steric hindrance to the binding of selpercatinib [ 136 , 159 ]. RET G810X mutations also mediate cross-resistance to pralsetinib [ 138 , 160 ]. Alternative roof solvent front mutations, such as RET L730V/I, have been identified in patients with pralsetinib-resistant tumors, while retaining sensitivity to selpercatinib in preclinical models [ 161 ].…”

Section: Acquired Resistancementioning

confidence: 99%

RET-Altered Cancers—A Tumor-Agnostic Review of Biology, Diagnosis and Targeted Therapy Activity

Desilets,

Repetto,

Yang

et al. 2023

Cancers

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RET alterations, such as fusions or mutations, drive the growth of multiple tumor types. These alterations are found in canonical (lung and thyroid) and non-canonical (e.g., gastrointestinal, breast, gynecological, genitourinary, histiocytic) cancers. RET alterations are best identified via comprehensive next-generation sequencing, preferably with DNA and RNA interrogation for fusions. Targeted therapies for RET-dependent cancers have evolved from older multikinase inhibitors to selective inhibitors of RET such as selpercatinib and pralsetinib. Prospective basket trials and retrospective reports have demonstrated the activity of these drugs in a wide variety of RET-altered cancers, notably those with RET fusions. This paved the way for the first tumor-agnostic selective RET inhibitor US FDA approval in 2022. Acquired resistance to RET kinase inhibitors can take the form of acquired resistance mutations (e.g., RET G810X) or bypass alterations.

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“…Pyrimidine, an aromatic N-heterocycle, is a widely distributed constituent found in natural compounds and plays a significant role in medicinal chemistry (see Figure for some examples) . Previous publications have highlighted the important binding interactions between pyrimidine-based ligands and protein targets. − The most frequent interaction in pyrimidine-based ligands is the hydrogen bond between the nitrogen atoms in the ring and the amino substituents attached to the pyrimidine nucleus. Theoretically, pyrimidine is a good modular scaffold incorporated into the library members.…”

mentioning

confidence: 99%

Design, Construction, and Screening of Diversified Pyrimidine-Focused DNA-Encoded Libraries

Seydimemet

Yang

et al. 2023

ACS Med. Chem. Lett.

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Pyrimidine is a ubiquitous component in natural products and approved drugs, providing an ideal modular scaffold for generating libraries with drug-like properties. DNA-encoded library technology introduces a novel library modality where each small molecule is covalently linked to a unique oligo tag. This technology offers the advantages of rapidly generating and interrogating large-scale libraries containing billions of members, substantially reducing the entry barrier to their use in both academia and the pharmaceutical industry. In this Letter, we describe the synthesis of three DNA-encoded libraries based on different functionalized pyrimidine cores featuring diversified chemoselectivity and regioselectivity. Preliminary screening of these DNA-encoded libraries against BRD4 identified compounds with nanomolar inhibition activities.

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Insights into pralsetinib resistance to the non-gatekeeper RET kinase G810C mutation through molecular dynamics simulations

Cited by 6 publications

References 63 publications

Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder–Decoder Model

Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder–Decoder Model

RET-Altered Cancers—A Tumor-Agnostic Review of Biology, Diagnosis and Targeted Therapy Activity

Design, Construction, and Screening of Diversified Pyrimidine-Focused DNA-Encoded Libraries

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