Jayapal Reddy Mallareddy
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View article: Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders
Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders Open
Despite ongoing efforts to employ structure-based methods to discover targeted protein degraders (TPD), the prevailing strategy remains synthesizing a focused set of heterobifunctional compounds and screening them for target protein degrad…
View article: Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors
Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors Open
Antibody-drug conjugates (ADCs) are increasingly used in clinic for multiple indications and may improve upon the activity of parental antibodies by delivering cytotoxic payloads into target cells. This activity is predicated upon internal…
View article: Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders
Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders Open
Despite ongoing efforts to employ structure-based methods to discover targeted protein degraders (TPD), the prevailing strategy continues to be the synthesis of a focused set of heterobifunctional compounds and screen them for target prote…
View article: The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax
The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax Open
Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL …
View article: DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation
DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation Open
Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an esse…
View article: FIGURE 6 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
FIGURE 6 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
SpiD3 prodrug (SpiD3_AP) displays antileukemic activity in Eµ-TCL1 mice. A, Synthesis of SpiD3_AP. Reagents and conditions (a) dimethyl amine (2 mol/L in MeOH), MeOH: DCM (2:1), 0°C. B, Spleen-derived malignant B cells from terminally dise…
View article: FIGURE 1 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
FIGURE 1 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
SpiD3 inhibits proliferation and induces apoptosis in malignant B cells. A, Chemical structures of analog 19 (monomer), SpiD3 and SpiD7 (dimers of analog 19). Full synthesis details reported elsewhere. B, Mitochondrial activity of CLL cell…
View article: Figure S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S2 shows the RNA-sequencing analysis of SpiD3-treated OSU-CLL cells.
View article: Figure S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S2 shows the RNA-sequencing analysis of SpiD3-treated OSU-CLL cells.
View article: FIGURE 5 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
FIGURE 5 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
SpiD3 synergizes with ibrutinib and elicits cytotoxic effects in ibrutinib-resistant CLL cells. A–D, Combination assays to test synergy between SpiD3 and ibrutinib (IBR; BTK inhibitor) in preclinical CLL models. HG-3 cells (A–B; n = 3 inde…
View article: Figure S4 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S4 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S4 shows SpiD3 inhibits CLL chemotaxis and induces transcription of UPR genes.
View article: Figure S7 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S7 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S7 shows SpiD3 spares healthy stromal and lymphoid cells.
View article: Figure S3 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S3 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S3 shows proteomic analysis of SpiD3-treated CLL cells using TMT-labeling.
View article: Table S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Table S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Table S2 is the list of primary antibodies used for immunoblotting assays in the study.
View article: Figure S8 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S8 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S8 shows the studies with SpiD3_AP in CLL.
View article: FIGURE 5 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
FIGURE 5 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
SpiD3 synergizes with ibrutinib and elicits cytotoxic effects in ibrutinib-resistant CLL cells. A–D, Combination assays to test synergy between SpiD3 and ibrutinib (IBR; BTK inhibitor) in preclinical CLL models. HG-3 cells (A–B; n = 3 inde…
View article: Data from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Data from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR).…
View article: Figure S1 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S1 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S1 shows the WGCNA-identified modules in SpiD3-treated OSU-CLL cells.
View article: FIGURE 4 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
FIGURE 4 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Antitumor effects of SpiD3 in patient-derived CLL samples. A, Viability of patient-derived CLL samples (n = 11–15) cocultured ex vivo with 9-15c mouse stroma cells for 48 hours was determined by Annexin-V/PI staining. Ibrutinib (IBR; 1 µmo…
View article: Figure S8 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S8 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S8 shows the studies with SpiD3_AP in CLL.
View article: FIGURE 3 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
FIGURE 3 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
SpiD3 induces the unfolded protein response and modulates CLL survival factors independent of TME stimuli. A, HG-3 and OSU-CLL cells were treated for 4 hours with SpiD3 (5, 10 µmol/L), thapsigargin (Thaps; 10 µmol/L), or equivalent DMSO ve…
View article: Figure S7 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S7 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S7 shows SpiD3 spares healthy stromal and lymphoid cells.
View article: Figure S3 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S3 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S3 shows proteomic analysis of SpiD3-treated CLL cells using TMT-labeling.
View article: Figure S5 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S5 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S5 shows SpiD3 inhibits cap-dependent protein translation in CLL cells.
View article: Data from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Data from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR).…
View article: Table S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Table S2 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Table S2 is the list of primary antibodies used for immunoblotting assays in the study.
View article: Figure S4 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Figure S4 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Figure S4 shows SpiD3 inhibits CLL chemotaxis and induces transcription of UPR genes.
View article: Table S1 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Table S1 from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Table S1 shows the characteristics of the patient-derived CLL samples used in the study.
View article: Supplementary Methods from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects
Supplementary Methods from Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects Open
Additional Methods