Anuradha I Illendula

US Patent:

20120059003, Mar 8, 2012

Filed:

May 13, 2010

Appl. No.:

13/320123

Inventors:

John H. Bushweller - Charlottesville VA, US
Jolanta Grembecka - Ann Arbor MI, US
Anuradha Illendula - Charlottesville VA, US
Lauren Dixon - Ann Arbor MI, US

Assignee:

UNIVERSITY OF VIRGINIA PATENT FOUNDATION - Charlottesville VA

International Classification:

A61K 31/5377
A61K 31/4439
A61P 35/02
C07D 211/14
A61K 31/4545
C07D 401/04
C07D 413/14

US Classification:

5142345, 5462734, 514338, 544124, 546194, 514318

Abstract:

This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in 12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBFβ-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBFβ and the CBFβ-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBFβ-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well selectivity for CBFβ-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines. Analysis of the pharmacokinetics of the developed compounds has made it possible to improve the lifetime of the compound in the plasma of mice to a level commensurate with long-term treatment.

US Patent:

20220387358, Dec 8, 2022

Filed:

Nov 9, 2020

Appl. No.:

17/775213

Inventors:

- Charlottesville VA, US
David J. Feith - Palmyra VA, US
Jennifer M. Pearson - Charlotte NC, US
Mark Kester - Afton VA, US
Tye Deering - Charlottesville VA, US
Todd Fox - Charlottesville VA, US
Helena Woodvine Snyder - Crozet VA, US
Anuradha Illendula - Crozet VA, US

International Classification:

A61K 31/164
A61K 31/635
A61K 31/706
A61K 9/127
A61K 9/00
A61P 35/02

Abstract:

Provided are methods for treating a disease, disorder, or condition associated with an acid ceramidase (AC) biological activity. The methods include administering to a subject in need thereof a composition including an AC inhibitor and at least one additional active agent, such as a C6-ceramide nanoliposome (CNL); an inhibitor of a Bcl-2 family protein; a hypomethylating agent; an intensive chemotherapeutic agent such as cytarabine (AraC) and/or daunorubicin; a Hedgehog pathway inhibitor; a targeted agent, such as a FLT2 inhibitor or a EDH1/2 inhibitor; and/or an antibody drug conjugate that targets, for example, CD-33. The composition can include N-[(2S,3R)-1,3-dihydroxyoctadecan-2-yl]2-chloroacetamide (SACLAC) or a pharmaceutically acceptable salt thereof and at least one additional active agent. The disease, disorder, or condition associated with the AC biological activity can be a cancer, such as acute myeloid leukemia (AML).

US Patent:

20190343820, Nov 14, 2019

Filed:

Jul 27, 2017

Appl. No.:

16/318041

Inventors:

- Charlottesville VA, US
Anuradha ILLENDULA - Crozet VA, US

International Classification:

A61K 31/4439
A61P 35/02
A61K 31/704

Abstract:

This invention relates to methods and compositions for treatment of inv(16) leukemia and particularly to treatment of acute myeloid leukemia. Disclosed is a method of treating inv(16) leukemia comprising the step of administering to a subject in need thereof a therapeutically effective combination of a) a compound of the formula (1) and b) a chemotherapeutic agent selected from the group consisting of pirarubicin, aclarubicin, mitoxantrone, doxorubicin, daunorubicin, idarubicin, epirubicin, cytarabine, pharmaceutically acceptable salts and mixtures thereof. The therapeutically effective combination synergistically inhibits proliferation of inv(16) leukemia cells. This invention also relates to pharmaceutical compositions comprising a therapeutically effective combination of the compound of formula (1) and the chemotherapeutic agent and a pharmaceutically acceptable excipient.

US Patent:

20170233375, Aug 17, 2017

Filed:

Aug 13, 2015

Appl. No.:

15/503188

Inventors:

- Charlottesville VA, US
Anuradha ILLENDULA - Crozet VA, US

Assignee:

UNIVERSITY OF VIRGINIA PATENT FOUNDATION - Charlottesville VA

International Classification:

C07D 405/04
C07D 235/18
C07D 401/04

Abstract:

This invention relates to compounds that bind to wild-type CBFβ and inhibit CBFβ binding to RUNX proteins. The potent compounds of the invention inhibit this protein-protein interaction at low micromolar concentrations, using allosteric mechanism to achieve inhibition, displace wild-type CBFβ from RUNX1 in cells, change occupancy of RUNX1 on target genes, and alter gene expression of RUNX1 target genes. These inhibitors show clear biological effects consistent with on-target RUNX protein activity. Pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable carrier represent a separate embodiment of the invention. Another embodiment of the invention are methods of treating a RUNX-signaling-dependent cancer that expresses wild-type CBFβ in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the cancer is selected from the group consisting of a RUNX-signaling-dependent leukemia that expresses wild-type CBFβ, lung cancer, bladder cancer, ovarian cancer, uterine cancer, endometrial cancer, breast cancer, liver cancer, pancreatic cancer, stomach cancer, cervical cancer, lymphoma, leukemia, acute myeloid leukemia, acute lymphocytic leukemia, salivary gland cancer, bone cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, skin cancer, melanoma, squamous cell carcinoma of the tongue, pleomorphic adenoma, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma, and/or adenocarcinoma. In another embodiment, the compounds of the invention can be used to treat a leukemia, lung cancer, ovarian cancer, and/or breast cancer.

US Patent:

20160096820, Apr 7, 2016

Filed:

Dec 14, 2015

Appl. No.:

14/967568

Inventors:

- Charlottesville VA, US
Jolanta Grembecka - Ann Arbor MI, US
Anuradha Illendula - Charlottesville VA, US
Lauren Dixon - Ann Arbor MI, US

International Classification:

C07D 401/04
C07D 235/18
C07D 405/04
C07D 401/14

Abstract:

This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in 12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBFβ-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBFβ and the CBFβ-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBFβ-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well as selectivity for CBFβ-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines. Analysis of the pharmacokinetics of the developed compounds has made it possible to improve the lifetime of the compound in the plasma of mice to a level commensurate with long-term treatment.

US Patent:

20140243331, Aug 28, 2014

Filed:

May 7, 2014

Appl. No.:

14/271978

Inventors:

John H. Bushweller - Charlottesville VA, US
Jolanta Grembecka - Ann Arbor MI, US
Anuradha Illendula - Charlottesville VA, US
Lauren Dixon - Ann Arbor MI, US

Assignee:

UNIVERSITY OF VIRGINIA PATENT FOUNDATION - Charlottesville VA

International Classification:

C07D 405/04
C07D 235/18
C07D 401/14
C07D 401/04

US Classification:

5142345, 514318, 514333, 514338, 514394, 544124, 546194, 546256, 5462734, 5483047, 5483107

Abstract:

This invention describes the development of targeted small molecule inhibitors of the inv(16) fusion, the causative agent in 12% of acute myeloid leukemia (AML). The inv(16) fusion results in expression of the CBFβ-SMMHC fusion protein in the blood cells of afflicted patients. The present invention provides compounds which inhibit the function of both CBFβ and the CBFβ-SMMHC fusion. These compounds block the growth of an inv(16) leukemia cell line as well as increase its apoptosis, while showing minimal effects against non inv(16) cell lines. As a mechanism to develop inhibitors with selectivity for the CBFβ-SMMHC fusion protein, the present invention further provides dimeric derivatives of these compounds which show both increased potency as well as selectivity for CBFβ-SMMHC. These compounds show potent inhibition of an inv(16) leukemia cell line with minimal effects on non inv(16) cell lines. Analysis of the pharmacokinetics of the developed compounds has made it possible to improve the lifetime of the compound in the plasma of mice to a level commensurate with long-term treatment.