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Publication Number
US-11938124-B2
Publication Date
2024-03-26
Expiration Date
Abstract
Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The present disclosure describes methods of recovering wild-type function to p53 mutants by treating a cancer with a compound and a second agent. The compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA and activate downstream effectors involved in tumor suppression. The disclosed compounds can be used in combination with a secondary agent to reduce the progression of cancers that contain a p53 mutation.
Core Innovation
The invention relates to a method of treating cancer in a subject in need thereof by administering a therapeutically-effective amount of a compound of a defined formula together with a therapeutically-effective amount of an immune checkpoint inhibitor. The compound is specified by substituent-variable constraints including R3 being H, R4 being a C4-C6-heterocyclyl substituted with at least halo-, R16 being hydrogen, and R17 being aryl substituted or unsubstituted, or a pharmaceutically-acceptable salt thereof.
The disclosure presents indole-based and other heteroaromatic core scaffolds with substituted heterocycle and aryl or heteroaryl regions, including halogen-containing substituents, alkyne-containing linkers, sulfonamide or sulfonyl motifs, and pharmaceutically acceptable salts. Non-limiting examples include morpholine-like, piperazine-like, piperidine-like, pyrrolidinyl, and related ring systems, as well as fluoro, chloro, and CF3 substituents.
The immune checkpoint inhibitor is described as anti-PD-1 or anti-PD-L1 agents, including nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, and durvalumab. Additional embodiments include mutant p53 context, including p53 Y220C, and embodiments for increasing anti-cancer activity related to mutant p53 reconforming.
Claims Coverage
The claim coverage centers on one independent method claim for treating cancer by co-administering a therapeutically-effective amount of a formula compound and a therapeutically-effective amount of an immune checkpoint inhibitor. The inventive features are grounded in the formula compound constraints on R3, R4, R16, and R17, with dependent claims refining the immune checkpoint inhibitor class or agent and further narrowing compound substituent scope.
Treating cancer with formula compound plus immune checkpoint inhibitor
A method of treating a cancer in a subject in need thereof by administering a therapeutically-effective amount of a compound of a specified formula, with R3 being H, R4 being a C4-C6-heterocyclyl substituted with at least halo-, R16 being hydrogen, and R17 being aryl substituted or unsubstituted, or a pharmaceutically-acceptable salt thereof, and administering a therapeutically-effective amount of an immune checkpoint inhibitor.
Immune checkpoint inhibitor selected from PD-(L)1 agents
The immune checkpoint inhibitor is refined to anti-PD-1 or anti-PD-L1 agents, including nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, and durvalumab.
Further constraining R17 aryl substituents
Dependent claims further define R17 as phenyl substituted or unsubstituted with substituents including sulfoxide, carboxyl, amide, amino, alkyl, alkoxy, hydroxy, heterocyclyl, halo, or cyano.
Mutant p53 Y220C context
Some dependent summaries include a mutant p53 embodiment identified as p53 Y220C.
Overall, the claim set defines combination cancer treatment using a structurally constrained formula compound and an immune checkpoint inhibitor, with dependent claims narrowing the inhibitor to PD-(L)1 agents and specific antibodies, and further refining compound substituent options and selected mutant p53 embodiments.
Stated Advantages
Increases stability of a biologically-active conformation of a p53 mutant when the indole-functionalized compound is present.
Restores wild-type function to mutant p53 by reconforming and/or stabilizing it into a DNA-binding, anti-cancer conformation.
Enables downstream tumor-suppression activities including p53-induced apoptosis, cell-cycle arrest, cellular senescence, and angiogenesis blockade.
Improved tumor growth inhibition, including strong TGI outcomes versus monotherapies.
Improved tumor regression, including reports of complete tumor regression or cure in the provided content.
Extended median survival time.
Acceptable tolerability, including minimal body weight loss and no major clinical toxicity in the provided content.
Combination therapy can improve survival as evaluated by a second median survival at least about 50% greater than a first median survival.
Documented Applications
Treating cancer in a subject in need thereof by administering the defined formula compound together with a therapeutically-effective amount of an immune checkpoint inhibitor.
Treating cancer, including ovarian cancer, breast cancer, and lung cancer.
Combination therapy using a specified indole-based compound with an anti-PD-1 agent in a mouse syngeneic MT373 sarcoma model, with tumor volume measurement in the study context.
In vivo efficacy testing in mouse syngeneic sarcoma models MT373 and MT245 for oral Compound 1 alone and in combination with an anti-PD-1 immune checkpoint inhibitor.
Increasing anti-cancer activity related to mutant p53 reconforming, including p53 Y220C, in combination with an additional anti-cancer agent acting via a non-p53-induced apoptosis pathway.
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