Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.

We designed and synthesized SKP2-recruiting degraders by linking SL1 to the BRD4 inhibitor JQ1...We further demonstrate that SKP2-directed PROTACs effectively degrade Androgen receptor (AR) in 22RV1 cells. These findings emphasize that SKP2, frequently overexpressed in various tumor cells, can be successfully exploited for TPD through non-covalent PROTACs, expanding the pool of E3 ligases available for potential therapeutic applications.

By integrating BRD4 ligands (JQ1, ABBV-075, and HJB97) with strategies like macrocyclization, dual-targeting designs, and the dTAG system, potency and isoform selectivity have been enhanced. The novel mechanism of molecular glue degraders is also explored. Multidimensional optimization is now propelling BRD4-PROTACs towards clinical translation, promising efficient, safe, and precisely controllable new strategies for cancer treatment.

HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment.

Here, we report that combining the BET inhibitor JQ1 with the autophagy inhibitor chloroquine (CQ) synergistically amplifies ERS, leading to enhanced ICD in OSCC models. This minimally invasive platform ensures sustained drug release, improves tumor accumulation, and minimizes systemic exposure. Our study not only elucidates a druggable autophagy-ERS-ICD axis but also provides a versatile transdermal delivery strategy with potential applicability to a range of solid tumors.

Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.

Using CD4 + T-cells from PWH on ART, there was a significant decrease in HIV DNA following administration of wortmannin (a pan-PI3K inhibitor), venetoclax (a Bcl2 inhibitor) and JQ1 (an LRA) when administered alone. Overall, reduction in the HIV reservoir by LRAs could be further enhanced in the presence of pro-apoptotic drugs, but the magnitude of the effect was modest, was dependent on the in vitro model used and for PI3K inhibitors, depended on the potency of latency reversal. These results are consistent with minimal additional efficacy in reservoir reduction when combining currently available LRAs and either PI3K inhibitors or venetoclax.

Using phenotype-driven screening, we identified a multi-target small-molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) that effectively reprograms human glioma cells into neuron-like cells by activating endogenous ASCL1 (174.4-fold) and remodeling the transcriptional landscape...In a subcutaneous xenograft model, brief pretreatment with DLC79 significantly attenuated the tumorigenic potential of glioma cells, reducing tumor bioluminescence by 56% and tumor mass by 47%. Our study establishes pharmacological reprogramming as a promising anti-glioma strategy that leverages neuronal conversion to reduce oncogenic properties, thereby initiating a novel therapeutic paradigm.

P3, N=460, Not yet recruiting, Novartis Pharmaceuticals

In biochemical assays, H5 shows IC50 = 7.9 ± 0.5 nM, outperforming JQ-1 (IC50 = 33.0 ± 1.0 nM) by 4-fold...In the HCT-116 xenograft mouse model, oral administration of H5 suppressed tumor growth (TGI = 82 % at 50 mg/kg) and downregulated the BRD4-driven oncoproteins c-MYC and BCL-2. Collectively, H5 emerges as a highly promising BRD4-targeted candidate for colorectal cancer treatment.

P1, N=3, Not yet recruiting, Novartis Pharmaceuticals

P1, N=24, Not yet recruiting, Novartis Pharmaceuticals