Nathan Kendsersky, Computational Biology Scientist, SK Life Science Labs
p300-selective degraders illustrate potent anti-tumor activity in a distinct subset of cancers
Abstract
p300/CBP are paralog lysine acetyltransferases known to regulate gene expression in part through their histone acetylation functions. Here we show that targeted p300-selective degraders demonstrate efficacy across several indications, including castrate-resistant prostate cancer and multiple solid tumor malignancies harboring synthetic lethal CBP mutations.
We discovered potent heterobifunctional degraders with clear selectivity for p300, exhibiting near complete degradation of p300 within 2 hours and no observable degradation of CBP through 48 h. Downstream pharmacology confirmed an on-target mechanism, with a rapid abrogation of H3K27 acetylation and potent growth inhibition observed only in CBP KO H1299 cells, but not in p300 KO or parental wild-type cells.
We tested our degraders across a panel of prostate cancer lines, where we found growth suppression of AR+ cells and a downregulation of c-myc as well as ARv7, two key drivers of prostate tumorigenesis. We further employed computational algorithms to define a subset of CBP alterations conferring a putative loss-of-function (LoF) phenotype and identified cell lines harboring the relevant mutations. Results in these endogenous lines recapitulated what we observed with our CBP KO cells, with potent growth inhibition seen in CBP LoF cell lines. We evaluated the response in mice harboring LOVO (CBP LoF) or VCaP (AR+ mCRPC) xenografts, which led to almost complete degradation of p300 within xenograft tumors, resulting in a pronounced inhibition of tumor growth.
Taken together, these results underscore the therapeutic potential of a selective p300 degrader in both castrate-resistant prostate and CBP LoF cancers.
We discovered potent heterobifunctional degraders with clear selectivity for p300, exhibiting near complete degradation of p300 within 2 hours and no observable degradation of CBP through 48 h. Downstream pharmacology confirmed an on-target mechanism, with a rapid abrogation of H3K27 acetylation and potent growth inhibition observed only in CBP KO H1299 cells, but not in p300 KO or parental wild-type cells.
We tested our degraders across a panel of prostate cancer lines, where we found growth suppression of AR+ cells and a downregulation of c-myc as well as ARv7, two key drivers of prostate tumorigenesis. We further employed computational algorithms to define a subset of CBP alterations conferring a putative loss-of-function (LoF) phenotype and identified cell lines harboring the relevant mutations. Results in these endogenous lines recapitulated what we observed with our CBP KO cells, with potent growth inhibition seen in CBP LoF cell lines. We evaluated the response in mice harboring LOVO (CBP LoF) or VCaP (AR+ mCRPC) xenografts, which led to almost complete degradation of p300 within xenograft tumors, resulting in a pronounced inhibition of tumor growth.
Taken together, these results underscore the therapeutic potential of a selective p300 degrader in both castrate-resistant prostate and CBP LoF cancers.