AZD5991

Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics.

The structural foundations for the design of MCL-1 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti-apoptotic proteins such as BCL-2, PROTAC strategies designed to degrade MCL-1, and reversible-binding chemotypes to maximize MCL-1 inhibition and minimize toxicity, are reviewed. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off-target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL-1 inhibition across various cancer contexts.

Finally, we found that hyper-immunogenicity may be sensitive to immunotherapy and certain drugs (AZD5991, Ibrutinib, Osimertinib, AGI-5198, Savolitinib, Sapitinib, AZ960, AZD3759 and Ruxolitinib), while PCI-34051 and Vorinostat showed sensitivity in patients with hypo-immunogenicity. Our results demonstrate that ICD plays an important role in UCEC progression, suggesting that ICD-related markers could serve as potential targets for prognosis and treatment.

In TCL models with dependence on MCL-1, combining CAR-37 T cells and the MCL-1 inhibitor AZD5991 increases anti-TCL response and prolongs survival of xenografted mice. These findings suggest that personalized selection of BH3 mimetic/CAR-T combinations could maximize the therapeutic index for patients with TCL and possibly other diseases.

Bcl-2 inhibitor ABT-737 and Mcl-1 inhibitor AZD5991 predisposed NVP-BEZ235-treated cells to transform into the apoptotic phenotype. PI3K inhibitor LY294002 and Stat3 inhibitor AG490 duplicated the sensitized actions towards NVP-BEZ235...Data of in vivo tumor-bearing studies further revealed a better anti-tumor potential in the combination treatment of NVP-BEZ235 and MEK/ERK inhibitors without obvious toxicity. Our findings suggest that the feedback activation of pro-survival machinery is likely to be the main cause of cancer cells being refractory to NVP-BEZ235, and a combination treatment is a feasible strategy to sensitize cancer cell responses.

High-risk patients responded better to AZD5991-1720, an MCL1 inhibitor, while low-risk patients showed improved responses to IGF1R-3801-1738, an IGF1R inhibitor, suggesting that risk stratification may help optimize treatment selection based on tumor-specific vulnerabilities...However, prospective validation is needed to confirm its clinical applicability. Potential limitations such as sample size and generalizability should be considered.

Accordingly, CD8 + T-LGLL cells from patients with enhanced MCL1 dependence significantly responded to AZD-5991 ex vivo while no response was observed in the remaining samples lacking enhanced MCL-1 dependence. Across clinically and genetically heterogeneous cases of T-LGLL, functional apoptosis profiling identified patients with CD8 + T-LGLL cells harboring a dominant dependence on MCL-1 as a potential therapeutic target.

The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound 6.22 This work reports the structure-based optimization of compound 6 into a series of BFL1 inhibitors selective over the other BCL2 family members, with low nanomolar cellular activity when combined with AZD5991, exemplified by compound 20. Compound 20 demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the in vivo study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound 20 stabilized the protein, extending the half-life to 10.8 h.

The development of mutant-selective BRAF inhibitors (BRAFi), like vemurafenib, has been efficacious in patients with metastatic melanoma, but the response rate is low for mutant BRAF PTC patients...We found that cells presenting with minority MOMP-like phenotypes are dependent on the apoptotic regulator, Mcl-1, as treatment with the Mcl-1 inhibitor, AZD5991, potently induced cell death in resistant cells. Furthermore, PI3K/AKT inhibitors sensitized resistant cells to BRAFi; an effect that was at least in part associated with reduced Mcl-1 levels. Together, these data implicate minority MOMP as a mechanism associated with intrinsic drug resistance and underscore the benefits of targeting Mcl-1 in mutant BRAF PTC.

Current standard of care for pTCL revolves around the chemotherapy regimens CHOP/E and for CD30-postive pTCLs, brentuximab vedotin is approved...Using the MCL-1 inhibitor AZD5991, we have shown statistically significant benefit in survival when combined with CHOP in 2 MCL-1 dependent preclinical pTCL PDX models (Koch et al...These data suggested that treatment with AD4573 either as a monotherapy or in combination with CHOP, would be an effective therapeutic strategy in pTCL. AZD4573 monotherapy is currently being evaluated in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK in patients with relapsed/refractory pTCL.

5µM, KS18 demonstrated efficacy against bortezomib-resistant MM cells, outperforming other Mcl-1 inhibitors in clinical trials such as S63845, VU661013, and AZD5991. According to these results, KS18 may be able to overcome resistance by concentrating on Mcl-1. These encouraging findings have prompted the development of many models of drug-resistant MM and AML for in vivo evaluation of this potential chemical.

Venetoclax is a selective BCL-2 inhibitor and is successfully used in CLL and AML, but heterogeneous sensitivity to venetoclax has been described in ALL and inhibitors of other BCL-2 family members including BCL-XL-selective A-1331852 and MCL-1 selective AZD5991 have been developed. Moreover, a dual inhibitor of the anti-apoptotic BCL-2 family members BCL-2 and BCL-XL (AZD4320) with its dendrimer conjugate (AZD0466) has recently shown anti-tumor activity in hematologic cancer models with manageable toxicity...Taken together, we found vulnerabilities of T-ALL to BCL-2 family inhibition, particularly to dual BCL-2/BCL-XL inhibition by AZD4320, and we demonstrated on-target activities. Using BH3-profiling, we identified BAD-priming as a marker of response for AZD4320 and MCL-1 dependence as a resistance mechanism that can be targeted by combination treatment, suggesting further clinical evaluation.