Oleandrin could potentially have therapeutic effects for NSCLC patients and possibly for other cancer types.

Using a scaffold hopping strategy from the reported AKT inhibitor AT-7867 (1) we pursued a series of structure activity relationship (SAR) studies that dramatically improved potency versus LATS1 and LATS2, while concurrently improving kinome-wide selectivity. ADME properties were further optimized via introduction of conformational restriction into the target molecule, to lead to compound 27 which possesses potent inhibitory activity against both LATS1 and LATS2 and proof of concept activity in wound healing models.

The subsequent in vitro evaluation of digitoxigenin and oleandrin derivatives 13a, 13g, 15a, and 15gdemonstrated that these four analogs reduced steady-state ATP1A1 levels in T98G cells in the 12-96 nM range. Interestingly, only the oleandrin analog 15g also lowered also steady-state levels of the cellular prion protein (PrPC), the main therapeutic target for the treatment of prion diseases.

Pedunculagin demonstrated the strongest binding energy and stability, making it a promising candidate for further development as a novel lead compound to disrupt STAT5a/b dimerization in PCa therapy.

P1, N=47, Terminated, Taiho Oncology, Inc. | N=100 --> 47 | Trial completion date: Jul 2027 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Apr 2025 --> Nov 2024; Taiho Oncology as the sponsor of study TAS0612-101, has made a strategic decision to terminate the TAS0612-101 study, taking into consideration the safety profile of TAS0612 and the absence of encouraging anti-tumor activity.

These anti-migratory and anti-invasive properties in integrin a3-silenced cells were associated with epithelial cadherin (E-cadherin) distribution at cell-cell contacts, and these effects require the activation of p70 S6 kinase (p70S6K) as evidenced by treatment with rapamycin...In contrast, enhanced proliferation in integrin a3-silenced cells was not affected by the changes in E-cadherin expression. These findings demonstrate the ability of integrin a3b1 to differentially regulate NSCLC cell growth and progression depending on the p53 status, and suggest that integrin a3b1-p70S6K-p53 network may be a promising target for the treatment of NSCLC.

P1, N=100, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2024 --> Apr 2025

Moreover, the combination of TAS0612 with venetoclax (VEN) showed the synergy in inducing apoptosis in HMCLs irrespective of the t(11;14) translocation status. TAS0612 alone and combined with VEN are new potent candidate therapeutic strategies for MM, regardless of cytogenetic/genetic profiles, facilitating its future clinical development.

These results suggest that OE and oleandrin are efficacious agents to treat canine atopic dermatitis. Future studies should evaluate the efficacy of these compounds in dogs affected by atopic dermatitis.

Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

The combined treatment of Oleandrin and radiotherapy demonstrated superior inhibition of tumor proliferation compared to either treatment alone. Our findings highlight Oleandrin as a novel and effective inhibitor of ATM and ATR kinase, offering new possibilities for the development of clinical radiosensitizing adjuvants.