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Title: Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors

Abstract

ERK is the effector kinase of the RAS-RAF-MEK-ERK signaling cascade, which promotes cell transformation and malignancy in many cancers and is thus a major drug target in oncology. Kinase inhibitors targeting RAF or MEK are already used for the treatment of certain cancers, such as melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination therapies targeting both RAF and MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector kinase ERK, making it a promising target for drug development efforts. Here, we report the design and structural/functional characterization of a set of bivalent ERK inhibitors that combine a small molecule inhibitor that binds to the ATP-binding pocket with a peptide that selectively binds to an ERK protein interaction surface, the D-site recruitment site (DRS). Our studies show that the lead bivalent inhibitor, SBP3, has markedly improved potency compared to the small molecule inhibitor alone. Unexpectedly, we found that SBP3 also binds to several ERK-related kinases that contain a DRS, highlighting the importance of experimentally verifying the predicted specificity of bivalent inhibitors. However, SBP3 does not target any other kinases belonging to the same CMGCmore » branch of the kinome. Additionally, our modular click chemistry inhibitor design facilitates the generation of different combinations of small molecule inhibitors with ERK-targeting peptides.« less

Authors:
 [1];  [1];  [2];  [2];  [2];  [1];  [2];  [1]; ORCiD logo [3]
  1. Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States
  2. Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, Florida 32827, United States
  3. Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States; Pathology Department, University of California San Diego, La Jolla, California 92093, United States
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409618
Report Number(s):
BNL-114670-2017-JA¿¿¿
Journal ID: ISSN 1948-5875
DOE Contract Number:
SC0012704
Resource Type:
Journal Article
Resource Relation:
Journal Name: ACS Medicinal Chemistry Letters; Journal Volume: 8; Journal Issue: 7
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; cancer; click chemistry; inhibitor; MAPK; melanoma; peptide; structure-based drug design

Citation Formats

Lechtenberg, Bernhard C., Mace, Peter D., Sessions, E. Hampton, Williamson, Robert, Stalder, Romain, Wallez, Yann, Roth, Gregory P., Riedl, Stefan J., and Pasquale, Elena B. Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors. United States: N. p., 2017. Web. doi:10.1021/acsmedchemlett.7b00127.
Lechtenberg, Bernhard C., Mace, Peter D., Sessions, E. Hampton, Williamson, Robert, Stalder, Romain, Wallez, Yann, Roth, Gregory P., Riedl, Stefan J., & Pasquale, Elena B. Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors. United States. doi:10.1021/acsmedchemlett.7b00127.
Lechtenberg, Bernhard C., Mace, Peter D., Sessions, E. Hampton, Williamson, Robert, Stalder, Romain, Wallez, Yann, Roth, Gregory P., Riedl, Stefan J., and Pasquale, Elena B. Tue . "Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors". United States. doi:10.1021/acsmedchemlett.7b00127.
@article{osti_1409618,
title = {Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors},
author = {Lechtenberg, Bernhard C. and Mace, Peter D. and Sessions, E. Hampton and Williamson, Robert and Stalder, Romain and Wallez, Yann and Roth, Gregory P. and Riedl, Stefan J. and Pasquale, Elena B.},
abstractNote = {ERK is the effector kinase of the RAS-RAF-MEK-ERK signaling cascade, which promotes cell transformation and malignancy in many cancers and is thus a major drug target in oncology. Kinase inhibitors targeting RAF or MEK are already used for the treatment of certain cancers, such as melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination therapies targeting both RAF and MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector kinase ERK, making it a promising target for drug development efforts. Here, we report the design and structural/functional characterization of a set of bivalent ERK inhibitors that combine a small molecule inhibitor that binds to the ATP-binding pocket with a peptide that selectively binds to an ERK protein interaction surface, the D-site recruitment site (DRS). Our studies show that the lead bivalent inhibitor, SBP3, has markedly improved potency compared to the small molecule inhibitor alone. Unexpectedly, we found that SBP3 also binds to several ERK-related kinases that contain a DRS, highlighting the importance of experimentally verifying the predicted specificity of bivalent inhibitors. However, SBP3 does not target any other kinases belonging to the same CMGC branch of the kinome. Additionally, our modular click chemistry inhibitor design facilitates the generation of different combinations of small molecule inhibitors with ERK-targeting peptides.},
doi = {10.1021/acsmedchemlett.7b00127},
journal = {ACS Medicinal Chemistry Letters},
number = 7,
volume = 8,
place = {United States},
year = {Tue Jun 13 00:00:00 EDT 2017},
month = {Tue Jun 13 00:00:00 EDT 2017}
}
  • Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor-enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1'-extendedmore » structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1' residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. Another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore, novel contacts, which were promising for inhibitor development, were identified, including a π-π stacking interaction between a pyridine ring and Tyr372.« less
  • Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor–enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1'-extendedmore » structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH 2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1' residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. In conclusion, another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore, novel contacts, which were promising for inhibitor development, were identified, including a π–π stacking interaction between a pyridine ring and Tyr372.« less
  • Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model,more » can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.« less