PCIP-1 is a PARP2 inhibitor. PCIP-1 recruits BET proteins to PARP2 to inhibit DNA repair, acts via event-driven pharmacology, and does not inhibit PARP-catalyzed PARylation. PCIP-1 inhibits DNA repair, thereby inducing synthetic lethality in homologous recombination-deficient cancer cells and increasing the sensitivity of PARP1 -knockout cells. PCIP-1 can be used in the research of homologous recombination-deficient cancers, T-cell acute lymphoblastic leukemia, and BRCA -mutant cancers [1].
In Vitro, PCIP-1 induces formation of a ternary complex between BRD4 bromodomain 1 and PARP1 catalytic domain in vitro, as measured by HTRF signal[1]. PCIP-1 (Up to 50 µM; 2 h pre-incubation with PCIP-1, followed by 45 min incubation with dBET6) shows weak, non-saturating engagement of BRD4 in Jurkat-BRD4-HiBit cells, with an EC50 of 26 µM, and its anti-proliferative activity is not driven by occupancy-based BRD4 inhibition[1]. PCIP-1 (1 nM-100 μM; 72 h) potently inhibits Jurkat T-cell viability with an IC50 of 662 nM, and its activity is enhanced over 14-fold (IC50 = 45 nM) in the presence of the DNA-damaging agent MMS[1]. PCIP-1 (1 µM; 4 h) induces proximity between BET proteins (BRD4) and PARP1/2 in 22Rv1 cells, as shown by increased co-immunoprecipitation of these protein pairs[1]. PCIP-1 (100 nM-10 µM; 24 h) inhibits repair of MMS-induced DNA damage and induces apoptosis in Jurkat cells, without inhibiting global PARP-catalyzed PARylation[1]. PCIP-1 (100 nM-1 µM; 24 h) induces S-phase cell cycle arrest in Jurkat cells, consistent with inhibition of DNA damage repair[1]. PCIP-1 (1 µM; up to 14 days) reduces the competitive fitness of PARP2-proficient Jurkat-Cas9 cells, such that PARP2-deficient cells are selectively enriched, demonstrating PARP2 dependence of PCIP-1 activity[1]. PCIP-1 (0.1 nM-10 μM; 6 days) exhibits synthetic lethality with BRCA2 deficiency in DLD1 colon cancer cells, with BRCA2K/O cells showing over 100-fold greater sensitivity than parental cells[1].
References:
[1]. Bryce da Camara, et al. Rewiring DNA repair with PARP-based chemical inducers of proximity. bioRxiv. July 31, 2025.
In Vitro, PCIP-1 induces formation of a ternary complex between BRD4 bromodomain 1 and PARP1 catalytic domain in vitro, as measured by HTRF signal[1]. PCIP-1 (Up to 50 µM; 2 h pre-incubation with PCIP-1, followed by 45 min incubation with dBET6) shows weak, non-saturating engagement of BRD4 in Jurkat-BRD4-HiBit cells, with an EC50 of 26 µM, and its anti-proliferative activity is not driven by occupancy-based BRD4 inhibition[1]. PCIP-1 (1 nM-100 μM; 72 h) potently inhibits Jurkat T-cell viability with an IC50 of 662 nM, and its activity is enhanced over 14-fold (IC50 = 45 nM) in the presence of the DNA-damaging agent MMS[1]. PCIP-1 (1 µM; 4 h) induces proximity between BET proteins (BRD4) and PARP1/2 in 22Rv1 cells, as shown by increased co-immunoprecipitation of these protein pairs[1]. PCIP-1 (100 nM-10 µM; 24 h) inhibits repair of MMS-induced DNA damage and induces apoptosis in Jurkat cells, without inhibiting global PARP-catalyzed PARylation[1]. PCIP-1 (100 nM-1 µM; 24 h) induces S-phase cell cycle arrest in Jurkat cells, consistent with inhibition of DNA damage repair[1]. PCIP-1 (1 µM; up to 14 days) reduces the competitive fitness of PARP2-proficient Jurkat-Cas9 cells, such that PARP2-deficient cells are selectively enriched, demonstrating PARP2 dependence of PCIP-1 activity[1]. PCIP-1 (0.1 nM-10 μM; 6 days) exhibits synthetic lethality with BRCA2 deficiency in DLD1 colon cancer cells, with BRCA2K/O cells showing over 100-fold greater sensitivity than parental cells[1].
References:
[1]. Bryce da Camara, et al. Rewiring DNA repair with PARP-based chemical inducers of proximity. bioRxiv. July 31, 2025.