Nuclear receptor modulators and their use for the treatment and prevention of cancer
Inventors
Neckers, Jane B. • Kim, Yeong Sang • Lee, Sunmin • Kumar, Vineet • Malhotra, Sanjay V.
Assignees
US Department of Health and Human Services
Publication Number
US-10737995-B2
Publication Date
2020-08-11
Expiration Date
2032-06-15
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed are compounds which are nuclear receptor modulators that can act as antagonists to the androgen receptor, for example, a compound of Formula I: wherein R1 to R5 and X1 to X5 are as described herein, as well as pharmaceutically acceptable salts, solvates, and stereoisomers thereof. Pharmaceutical compositions comprising such compounds, as well as methods of use, and treatment for cancers, including prostate cancers, other nuclear receptor mediated cancers, and other conditions, are also disclosed.
Core Innovation
The invention discloses compounds of Formula I that act as nuclear receptor modulators and specifically function as antagonists to the androgen receptor, including pharmaceutically acceptable salts, solvates, and stereoisomers thereof. These compounds can be formulated into pharmaceutical compositions and used in methods for treating or preventing cancers, especially prostate cancer, including advanced castrate-resistant prostate cancer (CRPC). The compounds operate by inhibiting AR activation, inducing AR degradation, and modulating other nuclear receptor pathways such as progesterone and estrogen receptors.
The problem addressed is the limitation of current therapies due to resistance to antiandrogen treatments in advanced prostate cancer. The increase in AR gene expression, often through gene amplification or mutation, contributes to this resistance. Existing first-generation AR antagonists like bicalutamide exhibit partial agonist properties in cells expressing high AR levels, which undermines therapeutic efficacy. Thus, there is an unmet need for second generation nuclear receptor modulators that retain antagonism even in the presence of excess or mutated AR.
The compounds of the invention provide a novel therapeutic approach by targeting Heat Shock Protein 40 (Hsp40), thereby indirectly regulating the androgen receptor pathway. Unlike approved antiandrogens or MDV3100 that bind directly to AR, these compounds remain effective against mutated AR forms common in advanced prostate cancer. They also inhibit genes in androgen-independent, AR-dependent pathways such as UBE2C, which current therapies do not inhibit, offering potential mechanisms to overcome drug resistance.
Claims Coverage
The patent includes one main independent claim directed to specific compounds of Formula I with defined substituents and structural characteristics, encompassing several pharmaceutically acceptable salts, solvates, and stereoisomers.
Specific compound structures
Compounds defined by Formula I, where R1 to R5 are selected from hydrogen, various alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, and other specified groups; X1 to X5 are hydrogen or electron withdrawing groups; and bond 'a' may be in the E or Z configuration, with certain provisos on substituent patterns.
Pharmaceutical compositions
Pharmaceutical compositions comprising a compound of Formula I or its salts, solvates, stereoisomers combined with pharmaceutically acceptable carriers, optionally including other antiandrogen or anticancer compounds.
Methods of treatment
Methods for treating or preventing cancer, notably prostate cancer and castrate-resistant prostate cancer, by administering effective amounts of a compound of Formula I or its salts, solvates, or stereoisomers.
Inhibition of androgen receptor activation
Methods of inhibiting AR activation, including androgen-independent AR activation, in a subject by administering compounds of Formula I.
Induction of androgen receptor degradation
Methods for inducing degradation of AR in prostate cancer cells using effective amounts of compounds of Formula I.
Modulation of other nuclear receptors
Methods of modulating nuclear receptors including progesterone receptor and estrogen receptor activation by administration of compounds of Formula I.
The claims cover novel compounds with specific structural features, pharmaceutical compositions that include these compounds, and therapeutic methods applying these compounds to modulate androgen receptor and related nuclear receptors for cancer treatment, particularly targeting forms resistant to existing antiandrogen therapies.
Stated Advantages
Compounds of the invention inhibit cancer through multiple mechanisms by targeting Hsp40, thus indirectly modulating the androgen receptor pathway.
They are effective against mutated androgen receptors common in advanced prostate cancer, unlike current antiandrogens which bind directly to AR.
The compounds inhibit androgen-independent, androgen receptor-dependent pathways, such as repression of UBE2C expression, which current therapies do not address.
Certain compounds show enhanced inhibition of AR nuclear translocation compared to bicalutamide.
Documented Applications
Treatment and prevention of prostate cancer, including advanced castrate-resistant prostate cancer.
Treatment and prevention of cancers mediated by nuclear receptors, including AR-dependent and AR-independent cancers.
Inhibition of androgen receptor activation and degradation in prostate cancer cells.
Modulation and inhibition of progesterone receptor and estrogen receptor activation.
Use in pharmaceutical compositions optionally combined with other antiandrogen or anticancer agents.
Interested in licensing this patent?