We establish NNMT as a central metabolic-immune hub that orchestrates TGF-β-mediated CD8⁺ T cell dysfunction and endothelial reprogramming in ccRCC.

Leveraging insights from the BRD4 inhibitor Y-803, we has developed MT-4561, which demonstrates high degradation activity and antitumor efficacy and is currently in Phase I clinical trials. These efforts exemplify a modality-driven drug discovery approach tailored to disease-specific pathologies, aiming to provide new therapeutic options for intractable diseases through the integration of scientific knowledge and technological innovation.

We discovered bromodomain-containing protein 4 (BRD4) degraders as novel antitumor therapeutics leveraging our internal knowledge on Y-803 (birabresib, OTX015/MK-8628), which was discovered by our company as the first-in-class BRD4 inhibitor. Since we had obtained rich structure-activity relationship (SAR) information on its core skeleton, thienodiazepine, we designed and optimized Von Hippel-Lindau (VHL)-based BRD4 degraders based on the thienodiazepine scaffold. Here, we report that we obtained a novel, best-in-class BRD4 degrader, which showed a potent antitumor effect in a xenograft model of acute myeloid leukemia (AML).

Compared to each drug alone, co-treatment with SNDX-5613 (revumenib) and FHD-286 or OTX015 and FHD-286 significantly reduced the in vivo AML burden and improved survival of the immune depleted mice, without inducing significant toxicity, in the xenograft models of MITR and MI-resistant PD MLL1-r AML cells. These findings highlight novel, targeted, drug combinations that overcome MI resistance in AML cells with MLL1-r or mtNPM1.

5. SHR6390 and OTX015 Synergistically Inhibit the Growth of AML Xenografts In Vivo.

In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.

MDA-NUT87 and MDA-NUT88 are the first stable human sinonasal NUT carcinoma cell lines established from the primary tumor site. They preserve the hallmark genetic and phenotypic characteristics of NUT carcinoma and show sensitivity to BET inhibition. These models represent valuable tools for mechanistic studies and high-throughput drug screening in sinonasal NUT carcinoma.

Bioinformatic analysis revealed that SRD5A1, a critical enzyme in androgen metabolism, is downregulated by the BRD4 inhibitor JQ1. This finding was validated using I-BET151, another BRD4 inhibitor, which also suppressed SRD5A1 expression in PCa cell lines. Furthermore, treatment with dutasteride (Duta), an SRD5A family inhibitor, significantly reduced both cell proliferation and invasion...Co-administration of BRD4 and SRD5A1 inhibitors yielded a more pronounced suppression of AR expression. These findings highlight the pivotal role of SRD5A1 in PCa progression and suggest that combinatorial inhibition of BRD4 and SRD5A1 may provide a more effective strategy for attenuating AR expression and halting disease development.

Finally, a deep-learning model for predicting the drug efficacy over patients' transcriptomic data revealed OTX015, a BET inhibitor, as a promising treatment that targets mutated FBXW7 PNI tumors. This study provides a rich resource for elucidating the molecular mechanisms of PNI tumors, laying a critical foundation for developing effective diagnostic and therapeutic strategies for PNI tumors in cervical cancer.

NHWD-870 exhibits anti-tumor activity both in vitro and in vivo against SCLC, primarily by regulating the BRD4/STRADA/CCND1 axis and inhibiting the transition of the cell cycle from the G1 phase to the S phase. These findings highlight the therapeutic potential of NHWD-870 as a novel BET inhibitor for SCLC treatment and provide a molecular basis for further clinical development.

In our study, osimertinib-resistant HCC827/OR and PC-9/OR cells were established from parental osimertinib-sensitive cells, and osimertinib (AZD9291) and NHWD870, a bromodomain and extra-terminal (BET) inhibitor, were used to treat cells and mice. Inhibition of BRD4 sensitized non-small-cell lung cancer (NSCLC) cells to osimertinib by blocking YAP1-mediated APT1 transcription and disrupting APT1-mediated depalmitoyation of MST1 and YAP1 nuclear translocation, which restores osimertinib sensitivity through the APT1-MST1-YAP1 axis in NSCLC. Our study provides a novel mechanism of osimertinib resistance and suggests potential therapeutic strategies for NSCLC.

CLEC4E+ TAMs promote an immunosuppressive microenvironment by enhancing their own proliferation and impairing anti-tumour functions, thereby limiting T-cell cytotoxicity. Targeting the BRD4/CEBPβ/CLEC4E axis with BET inhibitors represents a promising therapeutic strategy for reprogramming TAMs and enhancing anti-tumour immunity.