Paul G. Leonard
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View article: Evolution of chronic lymphocytic leukemia after allogeneic stem cell transplant
Evolution of chronic lymphocytic leukemia after allogeneic stem cell transplant Open
Allogeneic stem cell transplant (alloSCT) for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) can result in cure in some patients. Analogous to chemotherapy and targeted therapy, we hypothesized that allogeneic cellula…
View article: Supplementary information from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib
Supplementary information from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib Open
Supplementary Materials and Methods Supplementary References Tables S1 to S3 and legends Figures S1 to S4 and legends
View article: Supplementary information from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib
Supplementary information from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib Open
Supplementary Materials and Methods Supplementary References Tables S1 to S3 and legends Figures S1 to S4 and legends
View article: Data from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib
Data from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib Open
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated t…
View article: Data from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib
Data from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib Open
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated t…
View article: Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase
Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase Open
Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spect…
View article: Generation and Validation of an Anti-Human PANK3 Mouse Monoclonal Antibody
Generation and Validation of an Anti-Human PANK3 Mouse Monoclonal Antibody Open
Coenzyme A (CoA) is an essential co-factor at the intersection of diverse metabolic pathways. Cellular CoA biosynthesis is regulated at the first committed step—phosphorylation of pantothenic acid—catalyzed by pantothenate kinases (PANK1,2…
View article: CCDC 2191608: Experimental Crystal Structure Determination
CCDC 2191608: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: Generation and validation of an anti-human PANK3 mouse monoclonal antibody
Generation and validation of an anti-human PANK3 mouse monoclonal antibody Open
Coenzyme A (CoA) is an essential co-factor at the intersection of diverse metabolic pathways. Cellular CoA biosynthesis is regulated at the first committed step— phosphorylation of pantothenic acid—catalyzed by pantothenate kinases (PANK1,…
View article: Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site
Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site Open
Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critic…
View article: Discovery of 6-[(3 <i>S</i> ,4 <i>S</i> )-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor
Discovery of 6-[(3 <i>S</i> ,4 <i>S</i> )-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor Open
Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making t…
View article: Protein-Metabolite Interactomics Reveals Novel Regulation of Carbohydrate Metabolism
Protein-Metabolite Interactomics Reveals Novel Regulation of Carbohydrate Metabolism Open
Metabolism is highly interconnected and also has profound effects on other cellular processes. However, the interactions between metabolites and proteins that mediate this connectivity are frequently low affinity and difficult to discover,…
View article: GRB2 enforces homology-directed repair initiation by MRE11
GRB2 enforces homology-directed repair initiation by MRE11 Open
GRB2 controls radiation-induced DNA damage repair—a predictive biomarker for PARPi and radiation therapy outcome.
View article: Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme
Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme Open
Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed…
View article: Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties
Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties Open
Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical propertie…
View article: Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib
Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib Open
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated t…
View article: Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R
Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R Open
Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TA…
View article: Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation
Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation Open
Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to di…
View article: The 3S Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues
The 3S Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues Open
We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with a previously unknown mode of action, is a potent inhibitor of the glycolytic enzyme, Enolase. SF2312 can only be synthesi…
View article: Eradication of<i>ENO1</i>-deleted Glioblastoma through Collateral Lethality
Eradication of<i>ENO1</i>-deleted Glioblastoma through Collateral Lethality Open
Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is a potent inhibitor of the glycolytic enzyme Enolase with potential utili…
View article: The N-terminal domain of ALS-linked TDP-43 assembles without misfolding
The N-terminal domain of ALS-linked TDP-43 assembles without misfolding Open
TDP-43 forms inclusions in several neurodegenerative diseases, and both its N- and C-terminal domains are implicated in this process. We show that the folded TDP-43 N-terminal domain oligomerizes under physiological conditions and propose …