Evaluation of the Small-molecule BRD4 Degrader CFT-2718 in Small-cell Lung Cancer and Pancreatic Cancer Models

Abstract

Targeted, catalytic degradation of oncoproteins using heterobifunctional small molecules is an attractive modality, particularly for hematological malignancies which are often initiated by aberrant transcription factors and are challenging to drug with inhibitors. BRD4, a member of the Bromodomain and Extraterminal (BET) family, is a core transcriptional and epigenetic regulator that recruits the P-TEFb complex, which includes Cdk9 and cyclin T, to RNA polymerase II (pol II). Together, BRD4 and CDK9 phosphorylate serine 2 (pSer2) of heptad repeats in the C-terminal domain of RPB1, the large subunit of pol II, promoting transcriptional elongation. Small molecule degraders of BRD4 have shown encouraging efficacy in preclinical models for several tumor types, but less efficacy in other cancers including small cell lung cancer (SCLC) and pancreatic cancer. We here evaluated CFT-2718, a new BRD4-targeting degrader with enhanced catalytic activity and in vivo properties. In vivo, CFT-2718 has significantly greater efficacy than the CDK9 inhibitor dinaciclib in reducing growth of the LX-36 SCLC patient-derived xenograft (PDX) model and performed comparably to dinaciclib in limiting growth of the PNX-001 pancreatic PDX model. In vitro, CFT-2718 reduced cell viability in four SCLC and two pancreatic cancer models. In SCLC models, this activity significantly exceeded that of dinaciclib; further, CFT-2718 selectively increased the expression of cleaved Poly (ADP-ribose) polymerase PARP, an indicator of apoptosis. CFT-2718 caused rapid BRD4 degradation and reduced levels of total and pSer2 RPB1 protein. These and other findings suggest that BRD-mediated transcriptional suppression merits further exploration in the setting of SCLC.

Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy

“…This is supported by a recent study in which a new BRD4‐targeting degrader was identified to selectively increase the expression of cleaved Poly (ADP‐ribose) polymerase‐1 (PARP) and apoptosis in treatment‐refractory solid lung cancer. [ 36 ] It was also demonstrated that BET degraders such as ZBC260 and dBET can effectively induce Bim‐dependent apoptosisof human lung cancer cells via the suppression of Mcl‐1 and c‐FLIP. [ 18 ] Thus, it will be interesting to further explore the underlying mechanism of CREATE in controlling cancer cells and TAMs apoptosis.…”

Pathogenic role of super-enhancers as potential therapeutic targets in lung cancer

“…The novel BRD4-targeting agent CFT-2718 showed potent antitumor activity in xenograft mice. The intensity and duration of apoptosis induction and tumor proliferation inhibition by CFT-2718 surpassed that of the CDK kinase inhibitor dinaciclib in SCLC cells (Sun et al, 2021). OTX015 showed significant anti-cancer activity in NSCLC cells with or without EML4-ALK translocation and EGFR, KRAS mutations (Riveiro et al, 2016).…”

PROTAC therapy as a new targeted therapy for lung cancer

“… 48 , 49 , 50 CFT-2718 JQ-1 analog CRBN ligand BRD4 SCLC In vitro ; In vivo SCLC PDX Zong et al.48, Sun et al. 51 QCA570 QCA276 CRBN ligand BRD2, BRD3, BRD4 LUAD; LSCC In vitro ; In vivo HCC827/AR xenograft Qin et al. 52 ; Liu et al.…”

“… 46 Multiple BRD4 or pan-BRD PROTACs have been developed that showed promising antitumor efficacy in the xenograft tumors from EGFRi-resistant cell lines and lung cancer PDXs. 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 The protein tyrosine phosphatase SHP2 is frequently activated in lung cancer to maintain a fully activating oncogenic signaling and thus serves as an attractive therapeutic target. A potent SHP2 PROTAC, D26, was developed 54 and shown to have therapeutic efficacy alone, or in combination with the third-generation EGFR inhibitor, osimertinib, in blocking osimertinib-resistant lung cancer cells.…”