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-10071945-B2
Publication Date
2018-09-11
Expiration Date
2032-06-15
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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 provides novel compounds of Formula I that act as nuclear receptor modulators, specifically antagonists to the androgen receptor (AR), to treat and prevent cancers, including prostate cancer and advanced castrate-resistant prostate cancer (CRPC). These compounds, their pharmaceutically acceptable salts, solvates, and stereoisomers, along with pharmaceutical compositions containing them and methods of treatment, are disclosed. The compounds are characterized by specific substituents R1 to R5 and X1 to X5 as set forth in the structure, with defined chemical groups and conditions on their configurations.
The problem addressed by the invention is the resistance to existing antiandrogen therapies in advanced prostate cancer, particularly CRPC, which is associated with increased AR expression due to gene amplification or other mechanisms. Existing first-generation AR antagonists like bicalutamide demonstrate partial agonist activity in cells expressing elevated levels of AR, leading to treatment failure and the phenomenon known as antiandrogen withdrawal response. There is a need for new therapies that retain antagonistic activity even in cells with increased AR expression. The invention targets this unmet clinical need by providing compounds that inhibit cancer by multiple mechanisms, including modulating heat shock protein 40 kD (Hsp40) and affecting the AR pathway indirectly without binding directly to AR, thus overcoming mutation-driven resistance common in advanced prostate cancer.
Claims Coverage
The patent includes multiple independent claims covering methods of using compounds of Formula I to treat and modulate nuclear receptor activity, focused particularly on advanced prostate cancer and related nuclear receptors. The claims cover various aspects of treatment, modulation, and specific compound subsets.
Method of inhibiting androgen-independent androgen receptor activation
A method involving administering to a human subject an effective amount of a compound of Formula I to inhibit androgen-independent AR activation in prostate cancer.
Method of inhibiting progesterone receptor and estrogen receptor activation
Administration to a human subject of an effective amount of a compound of Formula I to inhibit activation of PR and/or ER.
Method of modulating heat shock protein 40 (Hsp40) activity
Administration to a human subject of an effective amount of a compound of Formula I to modulate Hsp40 activity.
Method of treating prostate cancer including castrate resistant forms
Administering an effective amount of a compound of Formula I to treat prostate cancer, including castrate resistant prostate cancer.
The independent claims collectively cover methods of treating prostate and other nuclear receptor-mediated cancers by using compounds of Formula I to inhibit androgen-independent AR activation, modulate PR and ER receptors, modulate Hsp40, and treat castrate-resistant prostate cancer, demonstrating the compounds’ broad therapeutic utility and mechanistic targets.
Stated Advantages
The compounds inhibit cancer via more than one mechanism, including targeting Hsp40 and indirectly modulating the androgen receptor pathway.
These compounds do not bind to androgen receptors directly, enabling efficacy against mutant androgen receptors common in advanced prostate cancer.
They inhibit androgen-independent, androgen receptor-dependent gene expression pathways (e.g., UBE2C) not inhibited by current antiandrogens or MDV3100.
Compounds effectively inhibit AR translocation to the nucleus and induce AR degradation in cancer cells.
Documented Applications
Treatment and prevention of prostate cancer, in particular advanced castrate resistant prostate cancer.
Treatment of AR-dependent cancers, AR-independent cancers, and androgen-independent AR-dependent cancers.
Inhibition of androgen receptor activation and induction of AR degradation in prostate cancer cells.
Treatment of nuclear receptor-mediated cancers including those involving progesterone and estrogen receptors.
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