REFERENCE TO A SEQUENCE LISTING SUBMITTED AS A TEXT FILE VIA EFS-WEB

The Sequence Listing submitted Apr. 24, 2020 as a text file named “222117 2050 sequ list ST25.txt,” created on Oct. 25, 2018, and having a size 9,823 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).

BACKGROUND

Understanding the molecular mechanisms involved genesis and maintenance of cancer, as well as developing therapies which may help prevent or manage cancerous growth continue to be active areas of research. Work over the last decade is providing evidence that at least certain kinds of cancers may depend on a single oncogene or oncogenic pathway for growth, proliferation and survival. Oncogene addiction describes a phenomenon according to which tumor cells become reliant on the activity of a particular oncogene and die once this activity is inhibited. (Vivanco, 2014; Weinstein, 2002; Weinstein and Joe, 2006). Many recent targeted cancer therapies exploit this concept (Lord and Ashworth, 2013; Luo et al., 2009). It is perhaps best exemplified by the successful use of imatinib in the therapy of chronic myelogenous leukemia (CML) (Druker et al., 2001). In CML, the major driver of tumorigenesis is the BCR-ABL fusion oncogene; imatinib inhibits the constitutively active BCR-ABL protein kinase, to which leukemic cells become addicted. Other successful examples include trastuzumab targeting ERBB2 addiction (Paik et al., 2008), and vemurafenib targeting BRAF addiction (Bollag et al., 2010; Chapman et al., 2011; Davies et al., 2002). The challenge is to find such key oncogenes. Even though large sets of genome and transcriptome data are available to facilitate the identification of driver mutations in cancer, true signals are often buried in a large number of passenger events.

Despite advances in cancer research, better treatment options, and identification of novel therapeutic targets are needed. These needs and other needs are satisfied by the present disclosure.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds useful to regulate, limit, or inhibit the expression of AVIL (advillin), methods of making same, pharmaceutical compositions comprising same, and methods of treating disorders associated with AVIL dysregulation using same. In aspects, the disclosed compounds, compositions and methods are useful for treating disorders or diseases in which the regulation, limitation, or inhibition of the expression of AVIL can be clinically useful, such as, for example, the treatment of cancer.

According to various aspects, the compounds comprise one of Compounds A-L:



In each case, the compound can include a pharmaceutically-acceptable salt, solvate, or polymorph thereof.

Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Also disclosed are methods for the treatment of an oncological disorder or disease associated with dysregulation of AVIL in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound or pharmaceutically acceptable salt thereof.

Also disclosed are methods for regulating, limiting, or inhibiting AVIL expression in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound or pharmaceutically acceptable salt thereof.

Also disclosed are methods for regulating, limiting, or inhibiting AVIL expression in at least one cell, comprising the step of contacting the cell with an effective amount of at least one disclosed compound or pharmaceutically acceptable salt thereof.

Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt thereof; a disclosed product of making, or a pharmaceutically acceptable salt thereof; or a disclosed pharmaceutical composition.

Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with dysregulation of AVIL in a mammal.

Also disclosed are methods for the manufacture of a medicament to regulate, limit, or inhibit AVIL expression in a mammal comprising combining at least one disclosed compound, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

Also disclosed are kits comprising at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and one or more of: (a) at least one agent known to regulate, limit, or inhibit AVIL expression; (b) at least one agent known to treat cancer; and (c) instructions for treating cancer and/or for administering the compound in connection with cancer therapy.

While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

