PLX51107

Here we show that the BET inhibitor PLX51107 potently suppresses the growth of NRAS -mutant AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations.

To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness.

By further introducing EBA and salicylaldehyde into PLX51107 (a noncovalent BETi), we generated lysine-reactive, irreversible (BDS1-4) and reversible (BDS5-6) BD1 covalent inhibitors. Importantly, BDS4 retained robust activity against fibrosis in cells and animals when compared to RVX-208 (a reported BD2-selective noncovalent inhibitor) which showed only marginal effects. Our work serves as a useful tool to delineate distinct functions of BD1 and BD2 in future studies.

P1/2, N=2, Terminated, Hannah Choe, MD | Completed --> Terminated; Sponsor decision

Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.

P1/2, N=2, Completed, Hannah Choe | Recruiting --> Completed | Phase classification: P1b/2 --> P1/2 | N=34 --> 2 | Trial completion date: Dec 2025 --> Sep 2023 | Trial primary completion date: Dec 2024 --> Sep 2023

In a heavily pre-treated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.

To study pharmacologic Brd4 inhibition in Tet2 KO mice, we utilized PLX51107, a structurally distinct BET inhibitor previously reported on by our laboratory...Our novel inducible double knockout mouse model of CH achieved simultaneous knockout of Brd4 and Tet2, which has never been investigated. Collectively, our data provides rationale for further pre-clinical investigation of BET inhibitors to prevent progression of Tet2 CH.

Objective: Standard of care drugs for rhabdomyosarcoma (RMS), such as vincristine and doxorubicin, have a high systemic toxicity and >70% of high-risk patients develop resistance... ARMS cell lines (RH4, RH30) were treated with BETi compounds (BMS-986158, PLX51107) using a 12-point serial dilution (2.6 nM-10 M)... Functional validation confirmed BETi's potential for in vivo ARMS studies. Ongoing clinical trials of the primary drug candidate, BMS-986158, in childhood cancers increases the likelihood of clinical trial opportunities in RMS. Our metastatic models demonstrate clinical relevance and BETi sensitivity, crucial for addressing the lack of established metastatic ARMS studies.

Since Cisplatin-resistant sublines of UCC (LTTs) are highly dependent on DDR and apoptosis resistance, we characterized response of LTTs and treatment naïve parental cells towards combined treatment with PLX51107 and the PARP inhibitor (PARPi) Olaparib. Applicability of PARPi may be extended to BRCA wild-type cancer patients by episensitation with PLX51107. Thus, this combination could be a promising therapeutic option for UC also for second line treat- ment after chemotherapy.

Conclusion s : Our data indicates that a) PLX51107 has an antitumor effect in CLL cells; b) the combinational treatment of Venetoclax with PLX51107 highly improved the apoptotic effect of single agent treatments. A better understanding of the key signaling pathways for CLL cells' proliferation and survival impacted by BRD4i in combination with Venetoclax would provide a proof-of-concept rationale for studies validating BRD4i as epigenetic approach to target BCR signaling in CLL.