Reference Detail

Ref Type

PMID

Authors

Melissa Dumble, Lizhong Xu, Romyr Dominique, Binbin Liu, Hong Yang, Mary-Kate McBrayer, Dafydd Thomas, Bruce Fahr, Hongju Li, Kuo-Sen Huang, Kimberly Robell, Chris Mulligan, Brandon Russo, Anna Puzio-Kuter, Thomas Davis, Binh Vu

Title

PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development

Journal	Vol	Issue	Date	Pages	Journal Short Title

URL

https://www.abstractsonline.com/pp8/#!/9325/presentation/4758

Abstract Text

Mutations in the TP53 gene are the most frequent somatic alterations in human cancer; approximately 50% of all human cancers possess mutations in TP53. Missense mutations in TP53 which result in a non-functional protein are the most frequently identified, these occur across the gene, however most hotspot mutations are localized within the DNA binding domain of the protein. Y220C is one such hotspot mutation, prevalent in ~1.8% of TP53 mutant tumors. PC14586 was structurally designed to bind tightly to a crevice within the mutant protein (KD~2.5 nM). It is the first orally bioavailable small molecule and selective reactivator of Y220C mutant p53 protein in clinical development. In Y220C mutant human cell lines, PC14586 was shown to stabilize the Y220C mutant in the wild type conformation, resulting in reactivation of p53 transcriptional activity and subsequent expression of its target proteins (e.g. p21, MDM2, Bax, PUMA). The reactivation of p53 function is highly selective to Y220C mutant cells and results in arrest of the cell cycle in vitro (IC50 ~0.230-1.8 μM). PC14586 has favorable pharmaceutical properties in pre-clinical species. In nude mice bearing Y220C mutant NUGC3 gastric cancer xenograft tumors, oral administration of PC14586 results in a dose responsive anti-tumor effect, with a target efficacious dose of 100 mg/kg daily resulting in approximately 80% tumor regression after 3 weeks. This anti-tumor effect was driven by a dose responsive pharmacodynamic modulation of the mutant p53 target. In human xenografts, PC14586 was shown to convert Y220C mutant to the wildtype conformation, resulting in activation of p53 transcription. This was demonstrated by the measurement of a p53 mRNA transcriptional signature and at the protein level by increases in p21 and MDM2 in the tumor and Macrophage Inhibitory Cytokine-1 (MIC-1) in both the tumor and plasma. In a C57Bl/6J syngeneic xenograft model bearing the Y220C mutation, administration of PC14586 at 100 mg/kg orally resulted in complete tumor cure in 80% of mice. PC14586 is well tolerated by pre-clinical species and possesses a favorable development profile. The safety and efficacy of PC14586 is currently being evaluated in a seamless Phase I/II clinical study that is a biomarker driven, solid tumor agnostic trial with patients whose tumor bears the Y220C TP53 mutation (NCT study identifier NCT04585750).

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PC14586	PC14586	7	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PC14586		PC 14586\|PC-14586\|Rezatapopt	p53 Activator 11	PC14586 is a small molecule that stabilizes TP53 Y220C and reactivates TP53 function, which may lead to cell cycle arrest and growth inhibition (AACR Annual Meeting Apr 2021, Session MS.LBA01, Abstract # LB006).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 Y220C	stomach cancer	predicted - sensitive	PC14586	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PC14586 treatment reactivated Tp53 function, resulted in 80% tumor regression after 3 weeks in cell line xenograft models of gastric cancer harboring TP53 Y220C (AACR Annual Meeting Apr 2021, Session MS.LBA01, Abstract # LB006).	detail...
TP53 Y220C	Advanced Solid Tumor	predicted - sensitive	PC14586	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PC14586 treatment reactivated Tp53 function and resulted in cell cycle arrest in cancer cell lines harboring TP53 Y220C in culture, and led to complete cure in 80% of syngeneic xenograft models (AACR Annual Meeting Apr 2021, Session MS.LBA01, Abstract # LB006).	detail...