An updated patent review of AKT inhibitors (2020 – present)

ABSTRACTIntroduction Proteinkinase B (Akt), an essential protein in the PI3K/Akt/mTOR signalingpathway, plays a crucial role in tumor progression. Over the past twoyears, different types of Akt modulators have continued to emerge inthe patent literature.Areascovered Thisreview focuses on the patent literature covering small moleculeinhibitors, peptides, PROTACs, and antisense nucleic acids targetingAkt from 2020 to present. Also, we discuss the outcomes of severalclinical trials, combination strategies for different mechanisms, andthe application of Akt regulators in other non-oncology indications.Our search for relevant information was conducted using variousdatabases, including the European Patent Office, SciFinder, andPubMed, from 01.2020 to 04.2023.Expertopinion In recent years, some combination therapeutic strategies involvingAkt inhibitors have shown promising clinical outcomes. Futureresearch can be directed toward developing new applications of Aktinhibitors, which may have implications for other diseases beyondcancer. New attempts suggest that targeting allosteric sites may be apotential solution to the problem of isoform selectivity.Furthermore, directly knocking out Akt protein by using the degraderssuggests a promising direction for future development.KEYWORDS: Akt;cancer;clinical trial;inhibitor;PROTAC;combinationDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsThe recent clinical advances of Akt inhibitors are described in this article.This review provides a comprehensive analysis of the structures and activity data of Akt inhibitors disclosed in patent applications from 2020 to present.In addition to traditional small molecule inhibitors, PROTACs and antisense nucleic acid drugs are also described in detail in this review.The combination of Akt inhibitors with tumor immunotherapy or other targeted therapies is emerging as a promising strategy.The Akt pathway plays a key role in non-cancerous diseases, which may broaden the clinical application of Akt inhibitors in the future.Declaration of interestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contribution statementXiaowu Dong and Jinxin Che conceived the review work and instructed the writing. Linjie Li and Yu Guo drafted the manuscript. Yang Lu and Yaping Xu collected the references and clinical trial information in this field. Yan Lu and Xiuping Zhu revised the manuscript. All the authors have read and agreed to the published version of the manuscript.AcknowledgmentsFigure 1, Figure 11, Figure 14 and Figure 15 were created with BioRender.com.Data availability statementThe authors confirm that the data supporting the findings of this study are available in the article from Pubmed at https://pubmed.ncbi.nlm.nih.gov. The patent and clinical data were derived from the following resources available in the public domain, SciFinder at https://scifinder-n.cas.org, European Patent Office at https://www.epo.org/and Clinical Trials.gov at https://clinicaltrials.gov/.Figure 1. Schematic overview of the PI3K/Akt pathway activation and regulation.Display full sizeFigure 2. Structures of compounds 16a, MK-HNE and 12l.Display full sizeFigure 3. Reported structures of Akt inhibitors in clinical trials.Display full sizeFigure 4. Structures of NTQ1062, example compound 2, 23, 41, 42 and universal structure from US20220226326A1.Display full sizeFigure 5. Representative structures of Hu7691 and compounds from WO2022121788A1.Display full sizeFigure 6. Structures of representative compounds from WO2021121276A1. (Note: Different linkers are marked as red and blue, respectively.)Display full sizeFigure 7. Representative structures of APN and Akt dual-target inhibitors in CN115232130A. (Note: The key pharmacophores of AZD5363 and bestatin are marked as red and blue, respectively. The middle 6 membered ring of compounds is marked as deep yellow.)Display full sizeFigure 8. Structures of representative compounds from WO2022068917A1.Display full sizeFigure 9. Structures of compounds from US20200148682A1 and WO2022069552A1.Display full sizeFigure 10. Structures of compounds from US20210137953A1, US20210113578A1 and WO2022005414A1. (Note: The 6-position carbon atom of triazolthiadiazine ring in compound 40 is marked as red.)Display full sizeFigure 11. The mechanism of Mcl-1/Akt inhibitor, PH-687.Display full sizeFigure 12. Reported structures of Akt degraders. (Note: The warhead, linker and E3-ligand are marked as blue, black and red, respectively. GR: growth rate inhibition. DC: degradation concentration.)Display full sizeFigure 13. Structures of compounds from WO2021030248A1.Display full sizeFigure 14. The combination mechanism of Akt and CAR-T.Display full sizeFigure 15. The role of Akt pathway in polycystic kidney disease and retinitis pigmentosa.Display full sizeTable 1. Ongoing clinical trials of Akt inhibitors.Table 2. Protein sequences of three fragments of OUN-36 (peptides 1-3, each fragment =24aa) [54].Additional informationFundingThis paper was funded by the National Natural Science Foundation of China (82003579, 81973172 and 82173660), the Natural Science Foundation of Zhejiang Province (LR21H300003 and LQ21H300005) and the Key R&D Program of Zhejiang Province (2023C03111).