birinapant (IGM-9427)

Birinapant in combination with CHK1 or AURKA inhibitors results in selective cell killing in RB-deficient TNBC models and yields durable disease control via apoptosis in vivo. In conclusion, RB loss in TNBC displays an enhanced vulnerability to pro-apoptotic signaling that can enable the effective implementation of new targeted therapeutic strategies.

The loss of USP13 significantly potentiates TNF-α/SMAC mimetic birinapant/pan-caspase inhibitor Z-VAD-FMK (TBZ)-induced necroptosis in CRC cells and diminishes tumor growth in a xenograft model. Thereby, USP13 may serve as a potential therapeutic target for anticancer treatment of CRC.

Reducing SMURF1, using a RIPK3 mutant defective in SMURF1-mediated ubiquitination, or overexpressing USP5 enhances necroptosis in leukaemia cells, leading to reduced tumour growth in xenograft models treated with birinapant and emricasan. These findings highlight the opposing regulation of K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis.

Our findings demonstrate enrichment of genes linked to chemotaxis and TNFR network of signals in the tumor cells and increased macrophage infiltration in the IBC tumor emboli microenvironment. Using a transgenic murine model, we demonstrate that treatment with Birinapant, a SMAC mimetic that enhances TNFα-mediated cell death, may be effective in targeting the tumor emboli phenotype.

Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade in vitro and/or in vivo. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility.

P1, N=272, Terminated, IGM Biosciences, Inc. | Trial completion date: Aug 2027 --> Jan 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2026 --> Jan 2025; Study terminated due strategic corporate pivot to focus on auto-immune indications

Furthermore, Birinapant positively affected oxidative stress maintenance, suggesting its potential role in promoting skin health and homeostasis. By demonstrating birinapant's efficacy, this research paves the way for further studies that could lead to the development of more effective therapies for psoriasis.

Finally, using both PDX and immunocompetent mouse models of GBM, we show that the SMAC mimetic birinapant, administered as an adjuvant after radiotherapy, can eliminate senescent GBM cells and prevent the emergence of recurrent tumors. Taken together, our results clearly indicate that significant improvement in GBM patient survival may become possible in the clinic by eliminating senescent cells arising after radiotherapy.

T-PLL cells exhibited a particular sensitivity to drugs targeting autophagy (thapsigargin, bafilomycin A1), nuclear export (selinexor), and inhibitor of apoptosis proteins (IAPs) (birinapant), sensitivities that were also shared by other T-cell malignancies. Through spectral flow cytometry we confirmed the absence of cleaved caspase-3 in IAP inhibitor treated T-PLL cells and show that IAP inhibition reduces the proliferation of T-PLL cells stimulated ex-vivo, while showing only a limited effect on non-malignant T-cells. In summary, our study maps the drug sensitivity of T-PLL across a broad range of targets and identifies new therapeutic approaches for T-PLL by targeting IAPs, XPO1 and autophagy, highlighting potential candidates for drug repurposing and novel treatment strategies.

Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial-mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment.

P1, N=272, Active, not recruiting, IGM Biosciences, Inc. | Recruiting --> Active, not recruiting | N=430 --> 272

Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.