Washington University

Robert H Mach

Zhude Tu

William G Hawkins

Wenhua Chu

Michael John Welch

Suwanna Vangveravong

Gregory Zipfel

Dirk Spitzer

Brian Van Tine

Byung Han

Richard S Hotchkiss

Rebecca Aft

Douglas J Rowland

Stanley M Parsons

Laura Dugan

Dong Zhou

Jonathan E McDunn

Jonathan McConathy

Wei Wang

Justin Rothfuss

Loren Michel

Delphine Chen

Douglas J Rowland, Jr

Richard A Hotchkiss

Mark Mintun

Wenhau Chu

Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described, such as the methanesulfonate salt of a compound of structural Formula IV, , wherein n is an integer chosen from 1, 2, 3, 4, and 5, and Ris H or methyl. At least one described molecular species exhibits an ICvalue below 5 &#x3bc;M against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo. It led to a 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.

Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof

The present disclosure provides compounds of structural Formula III: or a salt thereof, wherein Y is chosen from Further provided are pharmaceutical compositions comprising these compounds, and methods for treating cancer, such as pancreatic cancer or synovial sarcoma, using the compounds and compositions.

Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described. At least one described molecular species exhibits an ICvalue below 5 &#x3bc;M against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo, and led to 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.

Disclosed are PARP-1 inhibitors, which can beF-labeled for use as tracers in positron emission tomographic (PET) imaging. Further disclosed are methods of synthesis. Of the compounds synthesized, 2-[p-(2-Fluoroethoxy)phenyl]-1.3.10-triazatricyclo[6.4.1.0]trideca-2,4(13),5,7-tetraen-9-one (12) had the highest inhibition potency for PARP-1 (IC=6.3 nM). Synthesis of [F]-12 is disclosed under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET imaging using [F]-12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [F]-12 in a tumor. Binding, can be blocked by olaparib. The compounds have utility for tumor imaging.

Radiolabeled tracers for poly (ADP-ribose) polymerase-1 (PARP-1), methods and uses therefor

The present invention encompasses phenoxazine derivatives and methods of use thereof.

Phenoxazine derivatives and methods of use thereof

Tracers for imaging distribution of reactive oxygen species (ROS) are disclosed. The tracers include radiolabeled dihydroethidine (DHE) analogues. Further disclosed are uses of the compounds, including methods of imaging tissue distribution of ROS in vivo by positron emission tomography (PET). Methods of synthesizing the compounds are also disclosed.

Dihydroethidine analogues and uses thereof

Tracers for cationic amino acid transport systems and methods of synthesis are disclosed, including compounds comprising a 1H-[1,2,3]triazole moiety. Further disclosed are uses of the analogues, including in vivo imaging of tumors by Positron emission tomography (PET) or Single Photon Emission Computed Tomography (SPECT).

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Bipiperidinyl compounds and salts thereof are disclosed. The compounds include high affinity ligands for &#x3c3;receptors. Some compounds are also highly selective for &#x3c3;receptor compared to &#x3c3;receptor. Compounds can comprise radioisotopes, includingF orC. Radiolabeled compounds can be used as probes for imaging distribution of &#x3c3;receptor in a subject such as a human using positron emission tomography (PET) scanning.

Compounds comprising 4-benzoylpiperidine as a sigma-1-selective ligand

Pegylated fluoroalkoxybenzamide compounds which selectively bind Sigma-2 receptors are disclosed. These compounds, when labeled with a positron-emitting radioisotope such asF, can be used as radiotracers for medical imaging such as imaging of tumors by positron emission tomography (PET). In addition, these compounds, when labeled withI, can be used as radiotracers for imaging of tumors by single photon emission computed tomography (SPECT). Methods for synthesis of these compounds are also disclosed.

Pegylated fluorobenzamide analogues, their synthesis and use in diagnostic imaging

Novel isatin analogues, including isatin analogues comprising Michael Acceptors (IMAs) are disclosed. Further disclosed are methods of synthesis of the isatin analogues, and uses of the analogues, including inhibition of caspase-3 and caspase-7, and in vivo imaging of apoptosis by Positron emission tomography (PET) or Single Photon Emission Computed Tomography (SPECT).

Isatin analogues and uses therefor

Fluoroalkoxybenzamide compounds which selectively bind Sigma-2 receptors are disclosed. These compounds, when labelled withF, can be used as radiotracers for imaging of tumors by positron emission tomography (PET). In addition, these compounds, when labelled withI, can be used as radiotracers for imaging of tumors by single photon emission computed tomography (SPECT). Methods for synthesis of these compounds are also disclosed.

Radiolabelled fluorobenzamide analogues, their synthesis and use in diagnostic imaging

A series of N-substituted 9-azabicyclo[3.3.1]nonan-3&#x3b1;-yl phenylcarbamate analogs are disclosed, as well as methods of their preparation. Their affinities for sigma (&#x3c3;1 and &#x3c3;2) receptors are described. Two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3&#x3b1;-yl)-N'-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3&#x3b1;-yl)-N&#x2032;-(2-methoxy-5-methylphenyl)carbamate, are shown to have a high affinity and selectivity for &#x3c3;2 versus &#x3c3;1 receptors. Among the disclosed compounds are biotinylated and fluorescent analogs. These compounds can serve as probes to the &#x3c3;2 receptor. In addition, some disclosed compounds can induce apoptotic cell death by both caspase-dependent and caspase-independent mechanisms, and are effective for treatment of tumors. The compounds can be used as chemotherapeutics or chemosensitizers in the treatment of a wide variety of solid tumors.

Therapeutic uses of bicyclic ligands of sigma 2 receptor

Pharmaceutical compounds, pharmaceutical compositions and methods of treatment are disclosed, wherein a compound comprises a targeting moiety which, in free form, binds a cell receptor with a dissociation constant Kof less than about 10M, and a pharmaceutically active moiety, wherein the targeting moiety is other than an oligopeptide, a polypeptide, a peptidomimetic, a protein or a protein domain, and wherein the targeting moiety and the pharmaceutically active moiety are covalently attached. In some aspects, the targeting moiety binds a sigma-2 receptor with high affinity and high specificity, and the pharmaceutically active moiety is a pro-apoptotic peptide moiety. Methods of cancer treatment are disclosed comprising administering a disclosed pharmaceutical compound to a subject in need of thereof. The treatments selectively induce apoptosis in cancer cells. These methods can further comprise co-administration of radiation therapy and/or an additional chemotherapeutic agent.

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Eureka, MO, United States of America

Robert H Mach