Skip to main content

Advertisement

SpringerLink
Log in

Systematic profiling of staralog response to acquired drug resistant kinase gatekeeper mutations in targeted cancer therapy

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Kinase-targeted therapy has been widely used as a lifesaving strategy for cancer patients. However, many patients treated with targeted cancer drugs are clinically observed to rapidly develop acquired resistance. Kinase gatekeeper mutation is one of the most chief factors contributing to the resistance, which modulates the accessibility of kinase’s ATP-binding pocket. Previously, the pan-kinase inhibitor Staurosporine and its analogs (termed as Staralogs) have been reported to exhibit wild-type sparing selectivity for some kinase gatekeeper mutants, such as EGFR T790M, Her2 T798M and cSrc T338M. Here, we describe an integrative approach to systematically profile the molecular response of 15 representative Staralogs to 17 kinase gatekeeper mutations in targeted cancer therapy. With the profile we are able to divide gatekeeper mutations into three classes (i.e. classes I, II and III) and to divide Staralogs into two groups (i.e. groups 1 and 2) using heuristic clustering. The class I and II mutations confer consistent sensitivity and resistance for all Staralogs, respectively, while the class III mutations address divergent effects on different Staralogs. The mutations to Ile residue can generally reduce Staralog affinity by inducing unfavorable steric hindrance, whereas the mutations to Met and Leu residues would improve Staralog affinity by establishing favorable S···π interaction, van der Waals packing and/or hydrophobic contact. The group 1 and 2 Staralogs are primarily determined by carbonyl or hydroxyl substitution state at the position 7 of Staralog core, where points to kinase gatekeeper residue and can thus be directly influenced by gatekeeper mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ai X, Sun Y, Wang H, Lu S (2014) A systematic profile of clinical inhibitors responsive to EGFR somatic amino acid mutations in lung cancer: implication for the molecular mechanism of drug resistance and sensitivity. Amino Acids 46:1635–1648

    Article  CAS  PubMed  Google Scholar 

  • Ai X, Shen S, Shen L, Lu S (2015) An interaction map of small-molecule kinase inhibitors with anaplastic lymphoma kinase (ALK) mutants in ALK-positive non-small cell lung cancer. Biochimie 112:111–120

    Article  CAS  PubMed  Google Scholar 

  • Bai Z, Hou S, Zhang S, Li Z, Zhou P (2017) Targeting self-binding peptides as a novel strategy to regulate protein activity and function: a case study on the proto-oncogene tyrosine protein kinase c-Src. J Chem Inf Model 57:835–845

    Article  CAS  PubMed  Google Scholar 

  • Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV (2018) Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer 17:48

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bose P, Park H, Al-Khafaji J, Grant S (2013) Strategies to circumvent the T315I gatekeeper mutation in the Bcr-Abl tyrosine kinase. Leuk Res Rep 2:18–20

    PubMed  PubMed Central  Google Scholar 

  • Burotto M, Manasanch EE, Wilkerson J, Fojo T (2015) Gefitinib and erlotinib in metastatic non-small cell lung cancer: a meta-analysis of toxicity and efficacy of randomized clinical trials. Oncologist 20:400–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M (2006) BAY 43–9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98:326–334

    Article  CAS  PubMed  Google Scholar 

  • Chung LW, Sameera WM, Ramozzi R, Page AJ, Hatanaka M, Petrova GP, Harris TV, Li X, Ke Z, Liu F, Li HB, Ding L, Morokuma K (2015) The ONIOM method and its applications. Chem Rev 115:5678–5796

    Article  CAS  PubMed  Google Scholar 

  • Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 29:1046–1051

    Article  CAS  PubMed  Google Scholar 

  • Eck MJ, Yun CH (2010) Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta 1804:559–566

    Article  CAS  PubMed  Google Scholar 

  • Emrick MA, Lee T, Starkey PJ, Mumby MC, Resing KA, Ahn NG (2006) The gatekeeper residue controls autoactivation of ERK2 via a pathway of intramolecular connectivity. Proc Natl Acad Sci USA 103:18101–18106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giamas G, Stebbing J, Vorgias CE, Knippschild U (2007) Protein kinases as targets for cancer treatment. Pharmacogenomics 8:1005–1016

    Article  CAS  PubMed  Google Scholar 

  • Jänne PA (2008) Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours. Lung Cancer 60:S3–S9

    Article  PubMed  Google Scholar 

  • Lee HJ, Schaefer G, Heffron TP, Shao L, Ye X, Sideris S, Malek S, Chan E, Merchant M, La H, Ubhayakar S, Yauch RL, Pirazzoli V, Politi K, Settleman J (2013) Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov 3:168–181

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Yan F, Miao Q, Meng Y, Wen L, Jiang Q, Zhou P (2019a) Self-binding peptides: binding-upon-folding versus folding-upon-binding. J Theor Biol 469:25–34

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Miao Q, Yan F, Meng Y, Zhou P (2019b) Machine learning in quantitative protein-peptide affinity prediction: implications for therapeutic peptide design. Curr Drug Metab 20:170–176

    Article  CAS  PubMed  Google Scholar 

  • Liu T, Wang Z, Guo P, Ding N (2019) Electrostatic mechanism of V600E mutation-induced B-Raf constitutive activation in colorectal cancer: molecular implications for the selectivity difference between type-I and type-II inhibitors. Eur Biophys J 48:73–82

    Article  CAS  PubMed  Google Scholar 

  • Lopez MS, Choy JW, Peters U, Sos ML, Morgan DO, Shokat KM (2013) Staurosporine-derived inhibitors broaden the scope of analog-sensitive kinase technology. J Am Chem Soc 135:18153–18159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopez MS, Kliegman JI, Shokat KM (2014) The logic and design of analog-sensitive kinases and their small molecule inhibitors. Methods Enzymol 548:189–213

    Article  CAS  PubMed  Google Scholar 

  • Luo H, Du T, Zhou P, Yang L, Mei H, Ng H, Zhang W, Shu M, Tong W, Shi L, Mendrick DL, Hong H (2015) Molecular docking to identify associations between drugs and class I human leukocyte antigens for predicting idiosyncratic drug reactions. Comb Chem High Throughput Screen 18:296–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng S, Wu H, Wang J, Qiu Q (2016) Systematic analysis of tyrosine kinase inhibitor response to RET gatekeeper mutations in thyroid cancer. Mol Inform 35:495–505

    Article  CAS  PubMed  Google Scholar 

  • Mullard A (2015) Cancer drug developers counteract kinase gatekeeper mutations. Nat Rev Drug Discov 14:667–668

    Article  CAS  PubMed  Google Scholar 

  • Padma VV (2015) An overview of targeted cancer therapy. Biomedicine 5:19

    Article  PubMed  PubMed Central  Google Scholar 

  • Qin J, Xie P, Ventocilla C, Zhou G, Vultur A, Chen Q, Liu Q, Herlyn M, Winkler J, Marmorstein R (2012) Identification of a novel family of BRAFV600E inhibitors. J Med Chem 55:5220–5230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren Y, Chen X, Feng M, Wang Q, Zhou P (2011) Gaussian process: a promising approach for the modeling and prediction of peptide binding affinity to MHC proteins. Protein Pept Lett 18:670–678

    Article  CAS  PubMed  Google Scholar 

  • Rüegg UT, Burgess GM (1989) Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends Pharm Sci 10:218–220

    Article  PubMed  Google Scholar 

  • Song X, Liu X, Ding X (2017) Staurosporine scaffold-based rational discovery of the wild-type sparing reversible inhibitors of EGFR T790M gatekeeper mutant in lung cancer with analog-sensitive kinase technology. J Mol Recognit 30:e2590

    Article  CAS  Google Scholar 

  • Tan F, Shen X, Wang D, Xie G, Zhang X, Ding L, Hu Y, He W, Wang Y, Wang Y (2012) Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies. Lung Cancer 76:177–182

    Article  PubMed  Google Scholar 

  • Tian F, Lv Y, Zhou P, Yang L (2011) Characterization of PDZ domain-peptide interactions using an integrated protocol of QM/MM, PB/SA, and CFEA analyses. J Comput Aided Mol Des 25:947–958

    Article  CAS  PubMed  Google Scholar 

  • Tian F, Tan R, Guo T, Zhou P, Yang L (2013) Fast and reliable prediction of domain-peptide binding affinity using coarse-grained structure models. Biosystems 113:40–49

    Article  CAS  PubMed  Google Scholar 

  • Tian F, Yang C, Wang C, Guo T, Zhou P (2014) Mutatomics analysis of the systematic thermostability profile of Bacillus subtilis lipase A. J Mol Model 20:2257

    Article  PubMed  CAS  Google Scholar 

  • Wang YW, Zhang HY, Li JS, Wang XW (2017) Integrated exploitation of the structural diversity space of chemotherapy drugs to selectively inhibit HER2 T798M mutant in lung cancer. Chem Biodivers 14:e1600301

    Article  CAS  Google Scholar 

  • Wang Z, Jiang M, Feng N, Li C (2018) Fishing wild-type sparing inhibitors of proto-oncogene c-Met variants in renal cell carcinoma from a curated tyrosine kinase inhibitor pool using analog-sensitive kinase technology. Biochimie 152:188–197

    Article  CAS  PubMed  Google Scholar 

  • Yang C, Wang C, Zhang S, Huang J, Zhou P (2015a) Structural and energetic insights into the intermolecular interaction among human leukocyte antigens, clinical hypersensitive drugs and antigenic peptides. Mol Simul 41:741–751

    Article  CAS  Google Scholar 

  • Yang C, Zhang S, He P, Wang C, Huang J, Zhou P (2015b) Self-binding peptides: folding or binding. J Chem Inf Model 55:329–342

    Article  CAS  PubMed  Google Scholar 

  • Yang C, Zhang S, Bai Z, Hou S, Wu D, Huang J, Zhou P (2016) A two-step binding mechanism for the self-binding peptide recognition of target domains. Mol Biosyst 12:1201–1213

    Article  CAS  PubMed  Google Scholar 

  • Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ (2013) Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 19:2240–2247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Zhou P, Deng M, Shang Z (2014) Indirect readout in protein-peptide recognition: a different story from classical biomolecular recognition. J Chem Inf Model 54:2022–2032

    Article  CAS  PubMed  Google Scholar 

  • Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 105:2070–2075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang C, Lopez MS, Dar AC, Ladow E, Finkbeiner S, Yun CH, Eck MJ, Shokat KM (2013) Structure-guided inhibitor design expands the scope of analog-sensitive kinase technology. ACS Chem Biol 8:1931–1938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Jiao Y, Sun F, Liu X (2018) Revisiting the molecular mechanism of acquired resistance to reversible tyrosine kinase inhibitors caused by EGFR gatekeeper T790M mutation in non-small-cell lung cancer. Med Chem Res 27:2160–2170

    Article  CAS  Google Scholar 

  • Zhou P, Yang C, Ren Y, Wang C, Tian F (2013a) What are the ideal properties for functional food peptides with antihypertensive effect? A computational peptidology approach. Food Chem 141:2967–2973

    Article  CAS  PubMed  Google Scholar 

  • Zhou P, Wang C, Tian F, Ren Y, Yang C, Huang J (2013b) Biomacromolecular quantitative structure-activity relationship (BioQSAR): a proof-of-concept study on the modeling, prediction and interpretation of protein-protein binding affinity. J Comput Aided Mol Des 27:67–78

    Article  PubMed  CAS  Google Scholar 

  • Zhou P, Zhang S, Wang Y, Yang C, Huang J (2016) Structural modeling of HLA-B*1502 peptide carbamazepine T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome toxic epidermal necrolysis. J Biomol Struct Dyn 34:1806–1817

    Article  CAS  PubMed  Google Scholar 

  • Zhou P, Hou S, Bai Z, Li Z, Wang H, Chen Z, Meng Y (2018) Disrupting the intramolecular interaction between proto-oncogene c-Src SH3 domain and its self-binding peptide PPII with rationally designed peptide ligands. Artif Cells Nanomed Biotechnol 46:1122–1131

    Article  CAS  PubMed  Google Scholar 

  • Zhou P, Miao Q, Yan F, Li Z, Jiang Q, Wen L, Meng Y (2019) Is protein context responsible for peptide-mediated interactions? Mol Omics 15:280–295

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81874312) and the Research Foundation of Henan Province (Nos. 2018GGJS102 and 2017GGJS108).

Author information

Authors and Affiliations

  1. College of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China

    Yue Qiu, Xu Liu, Yanhua Liu, Yaling Yin & Peng Li

  2. School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China

    Yuping Yang

Authors
  1. Yuping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanhua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yaling Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yaling Yin or Peng Li.

Ethics declarations

Conflict of interest

None.

Additional information

Handling Editor: S. Dai.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Qiu, Y., Liu, X. et al. Systematic profiling of staralog response to acquired drug resistant kinase gatekeeper mutations in targeted cancer therapy. Amino Acids 52, 511–521 (2020). https://doi.org/10.1007/s00726-020-02832-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-020-02832-5

Keywords

Search

Navigation