Abstract: Aspects of the disclosure relate to compositions and methods for targeted protein degradation. In some embodiments, the disclosure relates to methods of evolving protein degrons to interact with certain small molecule inducers (e.g., VS-777, PT-179, or PK-1016). In some embodiments, the disclosure relates to compositions (e.g., peptides, nucleic acids encoding the protein degrons, etc.) used for targeted protein degradation. In some embodiments, the disclosure relates to methods of degrading a target polypeptide in a cell.

Abstract: This invention is related to molecules and methods of use of said molecules or compounds comprising said molecules. A molecule may be a pomalidomide or a thalidomide analogue. A method of inducing degradation of a target protein comprising one or more zinc finger polypeptides in a cell may comprise exposing a cell transfected with the target protein with a molecule as described herein, a pharmaceutically acceptable salt thereof, or any combination thereof. A method of inducing degradation of a target protein comprising one or more FK506 binding protein (FKBP) domains or degradation of a target amine in a cell may comprise exposing a cell transfected with the target protein or comprising the target amine with a composition comprising a molecule as described herein, a pharmaceutically acceptable salt thereof, or any combination of compositions comprising molecules as described herein and pharmaceutically acceptable salts thereof. A method may improve on-target effects and reduce off-target effects.

Abstract: The present inventions generally relate to site-specific delivery of nucleic acid modifiers and includes novel DNA-binding proteins and effectors that can be rapidly programmed to make site-specific DNA modifications. The present inventions also provide a synthetic all-in-one genome editor (SAGE) systems comprising designer DNA sequence readers and a set of small molecules that induce double-strand breaks, enhance cellular permeability, inhibit NHEJ and activate HDR, as well as methods of using and delivering such systems.

Abstract: The disclosure includes zinc prodrugs for targeted delivery of therapeutic, diagnostic or imaging agents to ?-cells and methods of use therefor. The disclosure also includes targeted delivery of small molecules to ?-cells that stabilize and activate CRISPR effector proteins comprising at least one destabilization domain, to enable CRISPR-based genome editing and transcriptional activation or repression in ?-cells.

Abstract: Systems, apparatuses, and methods for providing a more effective customer service support system. In some embodiments, the systems, apparatuses, and methods include a user interface (UI) and process flow for implementing a conversation-based customer service support system. The user interface and associated processing enable a user/customer to quickly and accurately select an intent, goal, or purpose of their customer service request. In some embodiments, this is achieved by a set of user interface displays or screens and an underlying logic that provide a user with multiple ways of selecting, identifying, or describing the intent, goal, or purpose of their request for service or assistance.

Abstract: Compositions and methods for conditionally regulating activities of CRISPR-Cas systems. In some embodiments, the methods comprise providing an inactive guide RNA comprising a regulatory domain bound by a lock nucleic acid different from the guide RNA; and displacing the lock nuclei acid from the regulatory domain by a trigger nucleic acid, thereby activating the guide RNA, wherein the activated guide RNA forms a complex with a Cas enzyme.

Abstract: The need to control the activity and fidelity of CRISPR-associated nucleases has resulted in the demand for inhibitory anti-CRISPR molecules. Current small-molecule inhibitor discovery platforms are not generalizable to multiple nuclease classes, only target the initial step in the catalytic activity, and require high concentration of nuclease, resulting in inhibitors with suboptimal attributes, including poor potency. Herein, Applicants report a high-throughput discovery pipeline consisting of a FRET-based assay that is generalizable to contemporary and emerging nucleases, operates at low nuclease concentration, and targets all catalytic steps. Applicants applied this pipeline to identify BRD7586, a cell-permeable small-molecule inhibitor of SpCas9, that is 2-fold more potent than current inhibitors. Furthermore, unlike the reported inhibitors, BRD7586 enhanced SpCas9 specificity and its activity was independent of the genomic loci, DNA repair pathway, or mode of nuclease delivery.

Abstract: The present disclosure relates to bifunctional chemical conjugation molecules, which find utility as modifiers of target substrates. The present disclosure includes multifunctional compounds comprising an enzyme binding moiety, a chemical linker moiety, and a target binding moiety, which may further include an electrophilic reactive group. Molecules according to the present invention find use making substrate modifications such as post-translational modifications to proteins that are not the natural substrate of the enzyme. Diseases or disorders may be treated or prevented with molecules of the present disclosure.

Abstract: Compositions and methods are provided for the inhibition of the function of RNA guided endonucleases, including the identification and use of such inhibitors.

Abstract: The embodiments disclosed herein utilize fluorescence polarization based preliminary screen to identify a putative set of Cas inhibitors from an initial set of candidate inhibitors. The primary screening assay is followed by secondary screening assay to validate the putative set of inhibitors selected by the preliminary screen. In some embodiments, the present disclosure includes compositions and methods are provided for the inhibition of the function of RNA guided endonucleases, including the identification and use of such inhibitors.

Abstract: The present disclosure relates to chimeric small molecules, which find utility as modifiers of target substrates according to the formula A-L1-E-B or A-L1-E-L2-B, wherein A is a kinase binding moiety; B is a target binding moiety; L1 and L2 are each a linker; and E is an electrophilic reactive group. Molecules according to the present invention find use making substrate modifications such as post-translational modifications to targets that are not the natural substrate of the kinase; accordingly, diseases or disorders may be treated or prevented with molecules of the present disclosure.

Abstract: A pharmaceutical composition comprising an effective amount of Dacomitinib as epidermal growth factor receptor (EGFR) inhibitor and a prostaglandin-Endoperoxide Synthase 2 (PTGS2) inhibitor, and one or more pharmaceutically acceptable excipients. A pharmaceutical composition comprising an effective amount of Dacomitinib as epidermal growth factor receptor (EGFR) inhibitor and an Adrenoceptor Beta 2 (ADRB2) inhibitor, and one or more pharmaceutically acceptable excipients. A method of treating pancreatic cancer, the method comprising the step of administering a therapeutically effective amount of the pharmaceutical composition to an individual in need thereof, the pharmaceutical composition comprising an effective amount of Dacomitinib as epidermal growth factor receptor (EGFR) inhibitor with a prostaglandin-Endoperoxide Synthase 2 (PTGS2) inhibitor or an Adrenoceptor Beta 2 (ADRB2) inhibitor, and one or more pharmaceutically acceptable excipients.

Abstract: A phosphoinositide 3-kinase inhibitor for use in the treatment of pancreatic cancer and a method for treatment of pancreatic cancer including administration of an phosphoinositide 3-kinase inhibitor an Src inhibitor to a human subject in need thereof. There is also provided a pharmaceutical composition comprising a phosphoinositide 3-kinase inhibitor and an Src inhibitor.

Abstract: A method for evaluating potential drug compositions for a target disease. The method includes providing a data input to a discovery engine, using the discovery engine to identify a first set of potential drug compositions for the target disease. The discovery engine is configured to analyze failed clinical assets of drugs for the target disease, wherein the discovery engine filters clinical trials which have failed due to non-drug safety related issues, perform differential gene expression analysis on normalized target-disease-related data, evaluate effect of known drugs used for diseases similar to the target disease, and perform a network-based analysis to identify repurposable drugs. Furthermore, asset prioritization is used to filter the first set of potential drug compositions to determine at least one potential drug composition for the target disease and validating the at least one potential drug composition for the target disease based on biological evidence and differential expression analysis.

Abstract: A method for determining combination drug and use in pancreatic cancer treatment, includes retrieving Pancreatic cancer datasets from a plurality of data sources based on selected types of expression profiling. A set of feature genes is determined based on differential gene expression analysis of disease samples and control samples in normalized pancreatic cancer datasets. Pancreatic cancer targets are selected for combination analysis based on druggability and determined set of feature genes. Based on node embedded clustering of the selected pancreatic cancer targets, synergistic target pairs is determined. Candidate pairs of drug combinations are selected from a plurality of pairs of drug combinations based on cumulative ranking score of each pair of drug combination and the synergistic target pairs.

Abstract: A phosphoinositide 3-kinase inhibitor for use in the treatment of pancreatic cancer and a method for treatment of pancreatic cancer including administration of an phosphoinositide 3-kinase inhibitor an Src inhibitor to a human subject in need thereof. There is also provided a pharmaceutical composition comprising a phosphoinositide 3-kinase inhibitor and an Src inhibitor.

Abstract: 3D cell cultures and devices for 3D cell culture, and methods of use thereof are provided. In some embodiments, the 3D cell culture comprise pancreatic ? cells and can be generated in multi-well plates, allowing for high throughput assays on the cell culture.

Abstract: Systems, apparatuses, and methods for providing a more effective customer service support system. In some embodiments, the systems, apparatuses, and methods include a user interface (UI) and process flow for implementing a conversation-based customer service support system. The user interface and associated processing enable a user/customer to quickly and accurately select an intent, goal, or purpose of their customer service request. In some embodiments, this is achieved by a set of user interface displays or screens and an underlying logic that provide a user with multiple ways of selecting, identifying, or describing the intent, goal, or purpose of their request for service or assistance.

Abstract: Systems, apparatuses, and methods for providing a more effective customer service support system. A trained model may be created or generated by a process that includes acquiring a corpus of documents (such as customer generated messages), generating keyphrases from each document in the corpus of documents, generating word embeddings from each document in the corpus of documents, performing a clustering operation on the word embeddings, assigning each document in the corpus to a duster and labeling each duster, and training a machine learning or text classification model using the most relevant documents in a cluster and the label assigned to that cluster. The methods include a processing flow that provides multiple ways for a customer to navigate and select their desired intent or purpose in seeking customer assistance. As part of the processing flow, the trained machine learning model and intent tree data are provided to a customer seeking assistance.

Abstract: The disclosure includes non-naturally occurring or engineered CRISPR Cas9, each associated with at least one destabilization domain (DD), along with compositions, systems and complexes involving the DD-CRISPR Cas9, nucleic acid molecules and vectors encoding the same, delivery systems involving the same, uses therefor.