Discovery of Clinical Candidate NTQ1062 as a Potent and Bioavailable Akt Inhibitor for the Treatment of Human Tumors

Ma, Chao; Wu, Jihuai; Wang, Lei; Ji, Xiaojun; Wu, Yebin; Miao, Lei; Chen, Donghui; Zhang, Linlin; Wu, Yi-nan; Feng, Haiwei; Tang, Ying; Zhou, Qinqin; Pei, Junjie; Yang, Xule; Xu, Dianguo; You, Qidong; Xie, Yuan

doi:10.1021/acs.jmedchem.2c00527

Cited by 11 publications

(11 citation statements)

References 24 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The selectivity of NTQ1062 was greater between AKT1 and AKT2 than between AKT1 and AKT3. The IC 50 of NTQ1062 for AKT1/2/3 was 1.6/24/0.3, respectively [ 47 ]. The important residues for AKT2 ligand binding were found to be Glu279 and Phe163, and the corresponding residues in AKT1 and AKT3 were not among the important binding residues.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Selectivity Studies and Free Energy Calculations of AKT Inhibitors

Zhong,

Goodwin

2024

Molecules

View full text Add to dashboard Cite

Protein kinase B (PKB) or AKT protein is an important target for cancer treatment. Significant advances have been made in developing ATP-competitive inhibitors and allosteric binders targeting AKT1. However, adverse effects or toxicities have been found, and the cutaneous toxicity was found to be linked to the inhibition of AKT2. Thus, selective inhibition of AKT inhibitors is of significance. Our work, using the Schrödinger Covalent Dock (CovDock) program and the Movable Type (MT)-based free energy calculation (ΔG), yielded small mean errors for the experimentally derived binding free energy (ΔG). The docking data suggested that AKT1 binding may require residues Asn54, Trp80, Tyr272, Asp274, and Asp292, whereas AKT2 binding would expect residues Phe163 and Glu279, and AKT3 binding would favor residues Glu17, Trp79, Phe306, and Glu295. These findings may help guide AKT1-selective or AKT3-selective molecular design while sparing the inhibition of AKT2 to minimize the cutaneous toxicity.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The important residues for AKT2 ligand binding were found to be Glu279 and Phe163, and the corresponding residues in AKT1 and AKT3 were not among the important binding residues. This helps to explain the weaker binding affinity of NTQ1062 toward AKT2 [ 47 ].…”

Section: Resultsmentioning

confidence: 99%

Selectivity Studies and Free Energy Calculations of AKT Inhibitors

Zhong,

Goodwin

2024

Molecules

View full text Add to dashboard Cite

show abstract

“…Extensive studies have showcased that NTQ1062 demonstrates favorable oral properties and exhibits dose-dependent pharmacodynamic effects in xenograft models exhibiting constitutive activation of the PI3K-Akt-mTOR pathway. 29 Presently, it is undergoing evaluation in a Phase I clinical trial for the treatment of advanced solid tumors (NCT06172309) and in a Phase Ib/II trial in combination with fulvestrant in patients with advanced HR+/HER2− breast cancer (NCT06172322). Capivasertib (AZD5363), developed by AstraZeneca in the early 2000s, is a potent, ATP-competitive Akt inhibitor with significant results as a therapeutic agent.…”

Section: Atp-competitive Akt Inhibitorsmentioning

confidence: 99%

“…NTQ1062 introduces a novel chemical scaffold, ( R )-5-methyl-5,8-dihydropyrido[2,3- d ]pyrimidin-7(6 H )-one, which binds to the hinge region of the kinase domain, and bears an optimized piperazine linker compared to ipatasertib (Chart ). Extensive studies have showcased that NTQ1062 demonstrates favorable oral properties and exhibits dose-dependent pharmacodynamic effects in xenograft models exhibiting constitutive activation of the PI3K-Akt-mTOR pathway . Presently, it is undergoing evaluation in a Phase I clinical trial for the treatment of advanced solid tumors (NCT06172309) and in a Phase Ib/II trial in combination with fulvestrant in patients with advanced HR+/HER2– breast cancer (NCT06172322).…”

Section: Atp-competitive Akt Inhibitorsmentioning

confidence: 99%

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

Pervanidis,

D’Angelo,

Weisner

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATPcompetitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments. ■ SIGNIFICANCE This Perspective highlights the pivotal role of Akt kinase in cancer and metabolic diseases. It focuses on the landmark FDA approval of capivasertib, a first-generation Akt inhibitor, for the treatment of breast cancer. It heralds the emergence of nextgeneration Akt inhibitors, allosteric and covalent-allosteric, that promise improved selectivity and potency, ushering in a new era of therapeutic strategies and personalized, more effective interventions.

show abstract

“…Excessive Akt activation is closely associated with the development of various malignant tumors, including breast cancer, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, and melanoma [ 8 ]. Currently, several ATP-competitive pan-Akt (Akt1, Akt2, and Akt3) inhibitors are active in the clinical stage, including capivasertib (AZD5363) [ 9 ], ipatasertib (GDC-0068) [ 10 ], afuresertib [ 11 ], and NTQ1062 [ 12 ]. Capivasertib has been approved by the FDA for the treatment of adult patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN -alterations in combination with fulvestrant.…”

Section: Introductionmentioning

confidence: 99%

A rapid and accurate method for evaluating the degradation of pan-Akt in cells by PROTACs using NanoLuc luciferase

Ji,

Miao,

et al. 2024

Biology Methods and Protocols

Self Cite

View full text Add to dashboard Cite

Proteolysis targeting chimeras (PROTAC) is a protein degradation technique that has been increasingly used in the development of new drugs in recent years. Akt is a classical serine/threonine kinase, and its role outside of the kinase has gradually gained attention in recent years, making it one of the proteins targeted by PROTACs. Currently there are many methods used for the evaluation of intracellular protein degradation, but each has its own advantages or disadvantages. This study aimed to investigate the feasibility of evaluating the degradation of pan-Akt proteins in cells by PROTACs (MS21 and MS170) using the NanoLuc luciferase method. After conducting a thorough comparison between this method and the classical western blot assay in various cells, as well as testing the stability of the experiments between multiple batches, we found that NanoLuc luciferase is a highly accurate, stable, low-cost and easy-to-operate method for the evaluation of intracellular pan-Akt degradation by PROTACs with a short cycle time and high cellular expandability. Given the numerous advantages of this method, it is hypothesized that it could be extended to evaluate the degradation of more target proteins of PROTACs. In summary, the NanoLuc luciferase is a suitable method for early protein degradation screening of PROTAC compounds.

show abstract

Discovery of Clinical Candidate NTQ1062 as a Potent and Bioavailable Akt Inhibitor for the Treatment of Human Tumors

Cited by 11 publications

References 24 publications

Selectivity Studies and Free Energy Calculations of AKT Inhibitors

Selectivity Studies and Free Energy Calculations of AKT Inhibitors

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

A rapid and accurate method for evaluating the degradation of pan-Akt in cells by PROTACs using NanoLuc luciferase

Contact Info

Product

Resources

About