Michele Mayo
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View article: Supplemental Table 5 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Table 5 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Table 5: Activity of KT-253 in AML patient-derived xenograft models.
View article: Supplemental Table 2 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Table 2 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Table 2: Genes and TaqMan Gene Expression Assay IDs used for RT-qPCR assays
View article: Supplemental Table 4 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Table 4 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Table 4: KT-253 shows potent growth inhibition and caspase activation across a panel of p53 wild-type hematologic cell lines.
View article: Supplemental Table 1 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Table 1 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Table 1: Cell lines and reagents
View article: Supplemental Figure 7 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Figure 7 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Figure 7: A single dose of KT 253 shows strong single-agent activity in a venetoclax resistant patient-derived AML model.
View article: Data from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Data from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors have demonstrated limited activity, underscoring an unmet need for a bet…
View article: Supplemental Figure 1 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Figure 1 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Figure 1: Chemical structures of (A) Compound 1, a KT 253 analog that lacks ability to engage cereblon (CRBN), (B) Compound 2, the warhead of KT 253 that engages MDM2, and (C) DS-3032, a small-molecule MDM2/p53 interaction inh…
View article: Supplemental Figure 3 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Figure 3 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Figure 3: Short term exposures with KT-253 sufficient for growth inhibition compared with MDM2 SMIs.
View article: Supplemental Figure 2 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Figure 2 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Figure 2: Targeted proteomics analysis of MDM2 levels in MV4;11 AML cells shows that 150 nM KT 253 can achieve degradation of MDM2 within 1 hour posttreatment.
View article: Supplemental Table 3 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Table 3 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Table 3: KT-253 shows picomolar growth inhibition potency compared with other MDM2 small molecule inhibitors.
View article: Supplemental Figure 4 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Figure 4 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Figure 4: A functional p53 is required for growth inhibition with KT-253.
View article: Supplemental Figure 6 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Figure 6 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Figure 6: KT 253 activity in p53 WT ABC subtype DLBCL model but not p53 mutated ABC subtype DLBCL model.
View article: Supplemental Figure 5 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
Supplemental Figure 5 from KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Supplemental Figure 5: A single dose of KT-253 more robustly induces p53 targets compared with exposure matched weekly dosing regimen.
View article: KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors
KT-253, a Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy than MDM2 Small-Molecule Inhibitors Open
Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors have demonstrated limited activity, underscoring an unmet need for a bet…
View article: Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases
Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases Open
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an …
View article: Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma
Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma Open
Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation pri…
View article: P464: PULSE DOSING OF POTENT AND SELECTIVE HETEROBIFUNCTIONAL MDM2 DEGRADER KT-253 DRIVES TUMOR REGRESSION AND DEMONSTRATES DIFFERENTIATED PHARMACOLOGY COMPARED TO P53/MDM2 SMALL MOLECULE INHIBITORS.
P464: PULSE DOSING OF POTENT AND SELECTIVE HETEROBIFUNCTIONAL MDM2 DEGRADER KT-253 DRIVES TUMOR REGRESSION AND DEMONSTRATES DIFFERENTIATED PHARMACOLOGY COMPARED TO P53/MDM2 SMALL MOLECULE INHIBITORS. Open
Background: The murine double minute 2 (MDM2) oncoprotein is a key E3 ubiquitin ligase that degrades the tumor-suppressor p53. Targeting of the MDM2/p53 interaction to stabilize p53 and induce apoptosis in wildtype (WT) p53 tumors is an em…
View article: Data from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Data from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
The promise of tumor-selective delivery of cytotoxic agents in the form of antibody–drug conjugates (ADC) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, …
View article: Table S3 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Table S3 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Extent of DNA adduct formation in EOL-1 (AML cells) exposed to the IGN diimine 7 or the monoimine 8 after a 5 h or 20 h exposure to the compounds
View article: Supplementary Methods from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Supplementary Methods from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Synthesis of IGNs
View article: Supplementary Figures S1-S5 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Supplementary Figures S1-S5 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Figure S1. Comparison of the rate of adduct formation of the indolinobenzodiazepine dimer 6 and the pyrrolobenzodiazepine dimer SJG-136 with dsDNA prepared from annealing of single strand DNA 3'-TATAGATCTATA-5'. Figure S2. A, In vitro pote…
View article: Supplementary Methods from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Supplementary Methods from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Synthesis of IGNs
View article: Table S2 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Table S2 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Comparative in vitro potency of IGNs with a diimine (1), monoimine (3), and diamine (2) towards hematologic and solid tumor cell lines
View article: Table S1 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Table S1 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Effect of substitution of an indolino moiety (6) for a pyrrolo group (SJG-136) on in vitro potency
View article: Supplementary Figures S1-S5 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Supplementary Figures S1-S5 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Figure S1. Comparison of the rate of adduct formation of the indolinobenzodiazepine dimer 6 and the pyrrolobenzodiazepine dimer SJG-136 with dsDNA prepared from annealing of single strand DNA 3'-TATAGATCTATA-5'. Figure S2. A, In vitro pote…
View article: Table S3 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Table S3 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Extent of DNA adduct formation in EOL-1 (AML cells) exposed to the IGN diimine 7 or the monoimine 8 after a 5 h or 20 h exposure to the compounds
View article: Table S1 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Table S1 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Effect of substitution of an indolino moiety (6) for a pyrrolo group (SJG-136) on in vitro potency
View article: Data from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Data from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
The promise of tumor-selective delivery of cytotoxic agents in the form of antibody–drug conjugates (ADC) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, …
View article: Table S2 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity
Table S2 from A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity Open
Comparative in vitro potency of IGNs with a diimine (1), monoimine (3), and diamine (2) towards hematologic and solid tumor cell lines
View article: Data from Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer
Data from Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer Open
PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been l…