1. Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics.

    ACS Chemical Biology 10(7):1667 (2015) PMID 25946900

    We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the ...
  2. Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells.

    PNAS 112(13):4044 (2015) PMID 25775525 PMCID PMC4386329

    Dendritic cells (DCs) are heterogeneous, comprising subsets with functional specializations that play distinct roles in immunity as well as immunopathology. We investigated the molecular control of cell survival of two main DC subsets: plasmacytoid DCs (pDCs) and conventional DCs (cDCs) and thei...
  3. The Functional Differences between Pro-survival and Pro-apoptotic B Cell Lymphoma 2 (Bcl-2) Proteins Depend on Structural Differences in Their Bcl-2 Homology 3 (BH3) Domains.

    Journal of Biological Chemistry 289(52):36001 (2014) PMID 25371206

    Bcl-2 homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members, although their ...
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  4. The functional differences between pro-survival and pro-apoptotic B cell lymphoma 2 (Bcl-2) proteins depend on structural differences in their Bcl-2 homology 3 (BH3) domains.

    Journal of Biological Chemistry 289(52):36001 (2014) PMID 25371206 PMCID PMC4276867

    Bcl-2 homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members, although their ...
  5. The Functional Differences between Pro-survival and Pro-apoptotic B Cell Lymphoma 2 (Bcl-2) Proteins Depend on Structural Differences in Their Bcl-2 Homology 3 (BH3) Domains.

    Journal of Biological Chemistry 289(52):36001 (2014) PMID 25371206 PMCID PMC4276867

    Bcl-2 homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members, although their ...
  6. The Functional Differences between Pro-survival and Pro-apoptotic B Cell Lymphoma 2 (Bcl-2) Proteins Depend on Structural Differences in Their Bcl-2 Homology 3 (BH3) Domains.

    Journal of Biological Chemistry 289(52):36001 (2014) PMID 25371206 PMCID PMC4276867

    Bcl-2 homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members, although their ...
  7. Apoptosis in schistosomes: toward novel targets for the treatment of schistosomiasis

    Trends in Parasitology 30(2):75 (2014)

    • Genomic and transcriptomic data have uncovered an intrinsic apoptosis pathway in schistosomes. • The schistosome intrinsic apoptosis pathway is similar to that i...
  8. Apoptosis in schistosomes: toward novel targets for the treatment of schistosomiasis.

    Trends in Parasitology 30(2):75 (2014) PMID 24393571

    Schistosomiasis is one of the world's major neglected tropical diseases. Recent advances in schistosome genomics and transcriptomics have identified components of an intrinsic, B cell lymphoma-2 (Bcl-2)-regulated apoptotic cell death pathway. Molecular characterization of this pathway demonstrat...
  9. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.

    Genes & Development 28(1):58 (2014) PMID 24395247 PMCID PMC3894413

    The transcriptional regulator c-MYC is abnormally overexpressed in many human cancers. Evasion from apoptosis is critical for cancer development, particularly c-MYC-driven cancers. We explored which anti-apoptotic BCL-2 family member (expressed under endogenous regulation) is essential to sustai...
  10. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.

    Genes & Development 28(1):58 (2014) PMID 24395247 PMCID PMC3894413

    The transcriptional regulator c-MYC is abnormally overexpressed in many human cancers. Evasion from apoptosis is critical for cancer development, particularly c-MYC-driven cancers. We explored which anti-apoptotic BCL-2 family member (expressed under endogenous regulation) is essential to sustai...
  11. Apoptosis in schistosomes: toward novel targets for the treatment of schistosomiasis

    Trends in Parasitology (2013)

    • Genomic and transcriptomic data have uncovered an intrinsic apoptosis pathway in schistosomes. • The schistosome intrinsic apoptosis pathway is similar to that i...
  12. Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.

    ChemBioChem 14(13):1564 (2013) PMID 23929624 PMCID PMC3970217

    We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal struc...
  13. Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.

    ChemBioChem 14(13):1564 (2013) PMID 23929624 PMCID PMC3970217

    We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal struc...
  14. Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL.

    Journal of medicinal and pharmaceutical chemistry 56(13):5514 (2013) PMID 23767404

    Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening campaign. Small struct...
  15. Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL.

    Journal of medicinal and pharmaceutical chemistry 56(13):5514 (2013) PMID 23767404

    Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening campaign. Small struct...
  16. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis.

    Cell 152(3):519 (2013) PMID 23374347

    In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oli...
  17. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis.

    Cell 152(3):519 (2013) PMID 23374347

    In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oli...
  18. Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis

    Cell 152(3):519 (2013)

    In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that indu...
  19. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia.

    Genes & Development 26(2):120 (2012) PMID 22279045 PMCID PMC3273836

    Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x(L) and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x(L), Bcl-2, or...
  20. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia.

    Genes & Development 26(2):120 (2012) PMID 22279045 PMCID PMC3273836

    Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x(L) and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x(L), Bcl-2, or...