Lucian DiPietro
A5005782428- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- Advanced Breast Cancer Therapies
- Click Chemistry and Applications
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- Microbial Natural Products and Biosynthesis
- Angiogenesis and VEGF in Cancer
- Synthetic Organic Chemistry Methods
- Chronic Lymphocytic Leukemia Research
- Phosphodiesterase function and regulation
- Marine Sponges and Natural Products
- Thyroid Cancer Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Kruppel-like factors research
- Synthesis and biological activity
- 14-3-3 protein interactions
- BRCA gene mutations in cancer
- Metal complexes synthesis and properties
- Synthesis and Reactions of Organic Compounds
- Wnt/β-catenin signaling in development and cancer
- Gastrointestinal Tumor Research and Treatment
- Signaling Pathways in Disease
- Insect Resistance and Genetics
Relay Therapeutics (United States)
2022-2023
Blueprint Medicines (United States)
2014-2022
Sage Therapeutics (United States)
2021
Eisai (United States)
2004-2009
Amgen (United States)
2007-2008
The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid (MTC), and papillary cancer. No approved therapies have been designed to target RET; treatment has limited multikinase inhibitors (MKI), which can significant off-target toxicities efficacy. BLU-667 a highly potent selective RET inhibitor overcome these limitations. In vitro, demonstrated ≥10-fold increased...
BLU-285 is a selective and potent mutant KIT PDGFRA inhibitor active in both preclinical clinical settings.
Inhibition of the VEGF signaling pathway has become a valuable approach in treatment cancers. Guided by X-ray crystallography and molecular modeling, series 2-aminobenzimidazoles 2-aminobenzoxazoles were identified as potent inhibitors VEGFR-2 (KDR) both enzymatic HUVEC cellular proliferation assays. In this report we describe synthesis structure−activity relationship benzoxazoles, culminating identification benzoxazole 22 selective inhibitor displaying good pharmacokinetic profile. Compound...
Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has intense interest developing agents suitable for modulating pathway vivo by targeting this enzyme pair. By utilizing a combination of structure-based design LipE-based structure efficiency relationships, core XAV939 was optimized into more stable, efficient, but less potent dihydropyran motif 7. This combined with elements screening hits 2, 19, 33 resulted highly potent, selective...
PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur the and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, prominently hyperglycemia due inhibition wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations cryo-electron microscopy identify an allosteric network that provides explanation for how mutations favor...
Overexpression of the antiapoptotic members Bcl-2 family proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe structure-based optimization a series N-heteroaryl sulfonamides that demonstrate potent mechanism-based death. The role acidic nature sulfonamide moiety as it relates potency, solubility, clearance examined. This has led discovery novel heterocyclic replacements for acylsulfonamide core ABT-737 ABT-263.
A series of naphthyl-based compounds were synthesized as potential inhibitors vascular endothelial growth factor (VEGF) receptors. Investigations structure-activity relationships led to the identification a naphthamides that are potent VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition VEGF-dependent human umbilical vein cell (HUVEC) proliferation, and these several possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48...
The synthesis and biological evaluation of potent selective PKD inhibitors are described herein. compounds in the present study selectively inhibit among other putative HDAC kinases. blunt phosphorylation subsequent nuclear export HDAC4/5 response to diverse agonists. These further establish central role as an kinase enhance current understanding cardiac myocyte signal transduction. vivo efficacy a representative example compound on heart morphology is reported
Abstract Introduction: RET/PTC1 was one of the first gene fusions identified from a solid tumor. In past 3 years, oncogenic RET have been in additional cancer types, most notably NSCLC and colon carcinomas. Activating germline mutations are also well established drivers multiple endocrine neoplasia while somatic prevalent alterations sporadic medullary thyroid cancers. light these findings, number approved multi-kinase inhibitors (mKIs) with vitro activity against wild-type (WT) RET, such as...
Abstract Introduction: CCDC6-RET/PTC1 (papillary thyroid cancer gene 1) was one of the first fusions identified from a malignant epithelial tumor. Over past 5 years, additional types have been found to oncogenic RET fusions, most notably non-small cell lung adenocarcinoma (NSCLC) and colorectal carcinoma (CRC). Activating mutations are also known drive multiple endocrine neoplasia prevalent type alteration in medullary (MTC). Multikinase inhibitors (mKIs) with vitro activity against RET,...
Abstract Background & Aims Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as driver of FLC pathogenesis. We aimed to assess whether tumors maintain dependency on this determine if PRKACA viable therapeutic target. Methods patient-derived xenograft (PDX) shRNA cell lines were implanted...
Abstract Phosphoinositide 3-kinase alpha (PI3Kα) is the most frequently mutated kinase in solid tumors. Traditionally, development of PI3Kα inhibitors has focused on active, or orthosteric site. The therapeutic index limited by lack clinically meaningful selectivity for mutant versus wild-type (WT) and off-isoform activity. Alpelisib, only approved inhibitor, emblematic class with toxicity related to inhibition WT other PI3K isoforms resulting sub-optimal reductions dose intensity frequent...
Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Chemotherapy has proven ineffective, and Sorafenib remains only approved targeted drug with no second or line treatment options. slows growth advanced liver cancers helps some patients live longer - by an average about three months. There a pressing need for more effective therapies. FGF19 highly controlled hormone normally expressed in intestine, that acts to regulate bile acid synthesis...
ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionDesign, Synthesis, and Evaluation of Orally Active Benzimidazoles Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase InhibitorsMichele H. Potashman, James Bready, Angela Coxon, Thomas M. DeMelfi, Jr., Lucian DiPietro, Nicholas Doerr, Daniel Elbaum, Juan Estrada, Paul Gallant, Julie Germain, Yan Gu, Jean-Christophe Harmange, Stephen A. Kaufman, Rick Kendall, Joseph L. Kim, Gondi N. Kumar, Alexander Long, Seshadri...
Abstract Inhibition of CDK4/6 combined with the estrogen receptor (ER) degrader fulvestrant significantly improves progression free survival and overall in advanced hormone positive (HR+) breast cancer patients is now standard care (SOC) this disease. Up to 40% HR+ cancers harbor PIK3CA mutations leading activation phosphoinositide 3-kinase alpha (PI3Kα), which has been associated resistance inhibitors fulvestrant. Therefore, PI3Kα inhibitor combinations and/or are high interest HR+, mutant...
<p>Time-dependence of biochemical inhibition and mutant selectivity RLY-2608</p>
<p>Activation loop residues 937-954 are more disordered in mutant vs. wildtype PI3Kα</p>
<p>PI3Kα KD Simulations</p>
<p>Body weight changes observed in vivo models upon treatment with RLY-2608</p>
<p>Body weight changes observed in vivo models upon treatment with RLY-2608</p>
<div>Abstract<p><i>PIK3CA</i> (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur the and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, prominently hyperglycemia due inhibition wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations cryo-electron microscopy identify an allosteric network...