Inhibitors of the USP1/UAF1 deubiquitinase complex and uses thereof
Inventors
Maloney, David J. • Rosenthal, Andrew S. • Jadhav, Ajit • Dexheimer, Thomas S. • Simeonov, Anton • Zhuang, Zhihao • Liang, Qin • Luci, Diane K.
Assignees
University of Delaware • US Department of Health and Human Services
Publication Number
US-9802904-B2
Publication Date
2017-10-31
Expiration Date
2033-12-26
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Abstract
Disclosed are inhibitors of the USP1/UAF1 deubiquitinase complex, for example. of formula (I), wherein R1, R2, and Q are as defined herein, which are useful in treating diseases such as cancer, and improving the efficacy of DNA damaging agents in cancer treatment. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the invention, a method of method of inhibiting a heterodimeric deubiquitinase complex in a cell, and a method of enhancing the chemotherapeutic treatment of cancer in a mammal undergoing treatment with an anti cancer agent. Further disclosed is a method of preparing compounds of the invention.
Core Innovation
The invention provides inhibitors of the USP1/UAF1 deubiquitinase complex, specifically compounds of formula (I), which include various substitutions for R1, R2, R3, R4, R5, and Q as defined within the patent. These compounds are useful in treating diseases such as cancer and improving the efficacy of DNA damaging agents in cancer treatment. The invention also encompasses pharmaceutical compositions containing these compounds, methods of inhibiting the USP1/UAF1 heterodimeric deubiquitinase complex in cells, and methods of enhancing chemotherapeutic cancer treatment by co-administering these compounds with anti-cancer agents.
The problem being addressed is the unmet need for new selective inhibitors of the USP1/UAF1 complex. Existing inhibitors like GW7647, Pimozide, and C527 suffer from limitations such as limited potency, off-target pharmacology, and low selectivity, which reduce their therapeutic usefulness. USP1/UAF1 plays crucial roles in DNA damage response pathways, such as translesion synthesis and the Fanconi anemia pathway, which are essential for repairing DNA damage caused by cross-linking agents commonly used in chemotherapy. Therefore, selective inhibition of USP1/UAF1 can sensitize cancer cells to DNA damaging agents, enhancing treatment efficacy.
The compounds described demonstrate selectivity for USP1/UAF1 over related deubiquitinases like USP2, USP5, USP7, USP8, and USP12/46, which suggests the ability to specifically target the USP1/UAF1 complex with reduced off-target effects. Synthetic methods for preparing these inhibitors are provided, and the inhibitors show reversible USP1/UAF1 inhibition, increase monoubiquitination of PCNA and FANCD2 in cells, and synergistically enhance cytotoxicity and reduce colony formation when combined with DNA damaging agents such as cisplatin, thereby illustrating their therapeutic potential in cancer treatment.
Claims Coverage
The patent includes four claims with one independent claim, detailing the compound, its pharmaceutical composition, and relevant derivatives and salts. The principal inventive features pertain to the specific chemical structure of the compound and its use in pharmaceutical compositions.
Compound of formula (I)
A compound specified by formula (I) where Q is an optionally substituted heteroaryl group; R1 is selected from aryl, heteroarylaryl, heteroaryl, and heterocyclyl optionally substituted with 1 to 5 specific substituents; R2 is selected from aryl, heteroaryl, and heterocyclyl, with optional substituents including halogens and alkyl groups; and R5 is hydrogen or optionally substituted alkyl, including deuterated derivatives and pharmaceutically acceptable salts thereof.
Pharmaceutical composition comprising the compound
A pharmaceutical composition containing a compound of formula (I), its deuterated derivatives, or pharmaceutically acceptable salts, together with a pharmaceutically acceptable carrier suitable for administration.
The claims mainly focus on the novel chemical entities defined by formula (I) and their pharmaceutical compositions, encompassing various substitutions and derivative forms to selectively inhibit the USP1/UAF1 complex, which supports therapeutic applications in cancer treatment and enhancement of chemotherapeutic agents.
Stated Advantages
Selective inhibition of the USP1/UAF1 complex over related deubiquitinases reduces off-target effects.
Enhanced efficacy of DNA damaging agents through sensitization of cancer cells, improving cancer treatment outcomes.
Reversible inhibition of USP1/UAF1 allows controlled modulation of enzyme activity.
Documented Applications
Treatment of cancer including non-small cell lung cancer and various other cancers by administering inhibitors of the USP1/UAF1 complex.
Enhancement of chemotherapeutic treatment in mammals undergoing treatment with DNA damaging agents such as cisplatin and mitomycin C through co-administration of the USP1/UAF1 inhibitors.
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