Viracept (nelfinavir)

P1, N=9, Completed, Mayo Clinic | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Nov 2023

P1/2, N=159, Completed, University of Oxford | Unknown status --> Completed | N=289 --> 159

Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

Additionally, repression of PPP2R1A enhances cellular susceptibility to nelfinavir-induced apoptosis and pyroptosis. Collectively, our findings indicated that meiosis-related genes might be therapeutic targets in LUAD and provided crucial guidelines for LUAD clinical intervention.

P1, N=18, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P2/3, N=671, Recruiting, Gilead Sciences | Active, not recruiting --> Recruiting

This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of relapsed and refractory MM. This was an overall negative study with no ORR observed. Fortunately, 1 patient experienced an SD response, allowing this combination to stabilize their disease until another novel therapy on a clinical trial was available.

P2/3, N=671, Active, not recruiting, Gilead Sciences

This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of RRMM. While no ORR was observed, identification of biomarkers used for selection of patients with no other SOC options who could experience at least SD responses may be beneficial in allowing this combination to slow or stabilize the disease progression until other novel therapies or clinical trials are available.

Further, nelfinavir exhibited therapeutic efficacy against T‑ALL in an SCL‑LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T‑ALL.

P2, N=36, Completed, AIDS Malignancy Consortium | Trial completion date: May 2022 --> Apr 2023

This talk will focus on early observations from Phase III Akt pathway inhibitor randomised trial (Nelfinavir), and HPV/PDL-1 biology within BIOEMBRACE study. The speaker will also focus on scheduling or timing of combination of anti PDL-1, AKT and VEGF inhibitors during chemoradiation and brachytherapy in ongoing trials and soon to be initiated EMBRACE studies in locally advanced high-risk and oligorecurrent setting.

Here in this study, we performed molecular docking against DDI2 with the 20 FDA-approved drugs and identified Alvimopan and Levocabastine as the top two compounds with the best binding score along with the standard drug Nelfinavir. MD simulation (100 ns) of these protein-ligand docked complexes reveals that the stability and compactness of Alvimopan are high in comparison with Nelfinavir. Our in-silico (Molecular docking and Molecular dynamics simulation) studies pointed out that Alvimopan may be repurposed as a DDI2 inhibitor and can be used as a potential anticancer agent for the treatment of brain tumors.Communicated by Ramaswamy H. Sarma.

The anti-retroviral agents nevirapine and nelfinavir suppressed proliferation and increased HERV-K expression in MM cell lines. Our results suggest that HERV-K is involved in MM progression, but its role is likely to go beyond promoting cell proliferation. Clarifying the role of HERV-K in MM will lead to the discovery of novel treatment strategies and supply new insights into MM pathogenesis.

Leveraging this knowledge, we develop an integrative pharmacogenomics pipeline to identify compounds similar to dipyridamole at the level of drug structure, cell sensitivity and molecular perturbation...We validate top-ranked compounds, nelfinavir and honokiol, and identify that low expression of the canonical epithelial cell marker, E-cadherin, is associated with statin-compound synergy. Analysis of remaining prioritized hits led to the validation of additional compounds, clotrimazole and vemurafenib. Thus, our computational pharmacogenomic approach identifies actionable compounds with pathway-specific activities.

Finally, we show that partial inhibition of the DDI2-protease domain with the antiviral drug nelfinavir increased bortezomib susceptibility in treated MM cells. Altogether, these findings define the DDI2-NRF1 pathway as an essential program contributing to proteasome inhibition responses and identifying DDI2 domains that could be targets of interest in bortezomib-treated MM patients.

The confidentiality and privacy of study participants will be maintained. The trial is registered with Clinical Trials Registry-India (CTRI/2017/08/009265) and ClinicalTrials.gov (NCT03256916).

High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.

High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.

P2, N=20, Terminated, University of Washington | N=120 --> 20 | Recruiting --> Terminated; Terminated due to slow accrual

Our findings highlight STAT3 as a promising therapeutic target. NFV is a novel anti-cancer drug for the treatment of non-small-cell lung cancer.

We combined proteome-wide affinity-purification of nelfinavir-interacting proteins with genome-wide CRISPR/Cas9-based screening to identify protein partners that interact with nelfinavir in an activity-dependent manner alongside candidate genetic contributors affecting nelfinavir cytotoxicity. Conversely, depletion of fatty acids/cholesterol pools by the FDA-approved drug ezetimibe showed a synergistic anti-cancer activity with nelfinavir in vitro. These results identify the modification of lipid-rich membranes by nelfinavir as a novel mechanism of action to achieve broad anti-cancer activity, which may be suitable for the treatment of PI-refractory multiple myeloma.

Sensitivity to nelfinavir was due to the IU-TAB-1 cell line's gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.

Our drug candidate pipeline identified known targeted drugs in breast cancer such as Tamoxifen and Fulvestrant, non-specific chemotherapies like doxorubicin in addition to the novel candidates Nelfinavir and Indinavir as potential therapeutic agents. In summary we identify key TFs in multiple cancers and novel drugs for targeting those TFs or downstream effectors.

Finally, the cleavage of caspases-3 and -7 and their downstream effector PARP, in association with increased pro-apoptotic protein BAX, indicated caspase-associated cell-death during NFV-mediated cytotoxicity. In summary, we demonstrated that HGSOC cells of differential platinum sensitivities could be therapeutically targeted by NFV via multipronged mechanistic approaches, encouraging its prospective repurposing benefit against HGSOC.

P2, N=120, Recruiting, University of Washington | Suspended --> Recruiting | Trial completion date: Dec 2021 --> Dec 2024 | Trial primary completion date: Dec 2021 --> Dec 2024

Metformin can inhibit the PI3K/Akt signaling pathway and synergizes with Nelfinavir to inhibit the proliferation and invasion of cervical cancer cells. Our results indicate that metformin mainly regulates the insulin signaling pathway and interferes with cell proliferation and apoptosis to inhibit proliferation and invasion of cervical cancer cells. These differentially expressed proteins may become new targets for the treatment of cervical cancer.

AZA-R subclones were next exposed to a set of inhibitors and followed the cell metabolism using WST1 assay in vitro, which revealed some previously not yet considered options (Sorafenib, Venetoclax, Dasatinib, Ruxolitinib, Panobinostat, Nelfinavir) to target AZA-R. Conclusion We herein present a well-characterized AZA-R cellular and PDX model. Preliminary evidence indicates the involvement of pro-survival pathway leading to AZA resistance.

Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir's effectiveness in the treatment of multiple myeloma.