imaradenant (AZD4635)

Besides, adenosine, cgs-15943, rolofylline, cvt-124, wrc-0571, luf-5834, cvt-6883, AZD-4635, cabozantinib, pazopanib, regorafenib, and sorafenib drugs were used as controls...Besides, the inhibition constants (Ki) values for purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: were lower compared with the controls Theoretical data suggest that purine and their derivatives 5: , 9: , 10: , 14: , 15: , 16: , and 20: could produce changes in cancer cell growth through inhibition of A1, A2-adenosine receptors and VEGFR-1 inhibition. These data indicate that these purine derivatives could be a therapeutic alternative to treat some types of cancer.

P1/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jan 2025 --> Jul 2025

P1/2, N=43, Active, not recruiting, MedImmune LLC | Phase classification: P1b/2 --> P1/2 | Trial completion date: Sep 2024 --> Jan 2025

No new or unexpected safety concerns were identified, and imaradenant had an acceptable safety profile at both 50- and 75-mg QD.

P1b/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jan 2024 --> Sep 2024

P2, N=59, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Apr 2023

P1, N=313, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Mar 2023

In addition, we propose that blocking tumor oxygen consumption using deferiprone (DFP), phenformin (Phen) and metformin (Met) will further enhance A2aR and PD-1/PD-L1 blockade efficacy. Both 4T1-HRE and E0771-HRE demonstrated increased luciferase activity that correlated with increasing doses of CoCl2 in vitro. Future experiments will focus on characterizing the adenosine pathway in vivo in 4T1-HRE and E0771-HRE tumors and examine how drugs that target the adenosine A2AaR receptor (AZD4635), and oxygen consumption (DFP, Phen and Met) influence tumor oxygen consumption in vivo as well as the activation states of immune cells in the tumor microenvironment.

P1b/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Dec 2022 --> Jan 2024

AZD4635 monotherapy or combination therapy was well-tolerated. Objective responses support additional phase 2 combination studies in mCRPC patients.

P1, N=313, Active, not recruiting, AstraZeneca | Trial completion date: Jul 2022 --> Dec 2022

P1b/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: May 2022 --> Dec 2022

Our results demonstrate that AAR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for AAR blockade. Inhibition of AAR signaling restores T cell function and proliferation. Furthermore, AAR and dual AAR/AAR antagonists showed similar or better results than AAR antagonist AZD-4635 reinforcing the idea of dominant role of the AAR in the regulation of the immune system.

Blocking the in vivo formation and function of eAdo in IOTResi tumors, using a combination of anti-CD73 antibody (2C5, murine IgG1-Fc) and an inhibitor of Adora2a (AZD4635) reduced the presence of eAdo, slowed tumor growth and reduced the lung metastatic burden. In addition, blocking the adenosine pathway improved the efficacy of combinations of cytotoxics (gemcitabine/ATR inhibitor) and immunotherapy (aCD40/anti-PDL1Ab).The formation of eAdo appears to be a factor in the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway using a CD73Ab and an Adora2ai may represent a strategy to modulate the PDAC stroma and improve therapy response in patients with PDAC.

The efficacy of AZD4635 versus aCD73 plus AZD4635 was evaluated in an in vivo castration-sensitive model of Pten-null prostate cancer treated with apalutamide plus androgen deprivation therapy via surgical castration. Moreover 75% (6/8) of mice treated with aCD73/AZD4635 had tumor burden reductions greater than 30% relative to vehicle treated controls versus 28.6% (2/7) of mice in the AZD4635 only group. Our findings show that extracellular adenosine is a key immunosuppressive molecule in PTEN-deficient prostate cancer and provide evidence that implicates adenosinergic signaling via CD73 as a contributing factor to decreased efficacy of A2aR blockade and progression to CRPC.

AT-004 inhibited NECA-mediated A2aR activation with a potency over 100-fold higher than SMIs e.g. AZD4635. AT-004 is a potent, selective and highly potent antagonist of A2aR receptor. Considering its potential safety advantage as an mAb comparing to most known A2aR SMI antagonists in that it does not cross the blood brain barrier, AT-004 maybe a promising novel therapeutic candidate for immunotherapy, vital for enhancing anti-tumor responses in solid tumors that show an incomplete response or resistance to anti-PD-1 or anti-PD-L1 mAb treatment due to elevated adenosine level in tumor microenvironment (TME).

P1, N=313, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2021 --> Jul 2022

P1b/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: May 2021 --> May 2022

However, when AZD4635/aCTLA4 was used as neoadjuvant therapy to AR inhibition with the anti-androgen apalutamide, it improved median survival time from 21 days in monotherapy treated mice to 34 days in AZD4635/aCTLA4 treated mice. These results provide preclinical evidence to support the rational combination of A2AR blockade with AZD4635 and aCTLA4 immune checkpoint inhibition for PTEN-deficient prostate cancer.

P1b/2, N=43, Active, not recruiting, MedImmune LLC | N=98 --> 43

P1, N=313, Active, not recruiting, AstraZeneca | Trial completion date: Mar 2021 --> Dec 2021

P1b/2, N=98, Active, not recruiting, MedImmune LLC | Trial completion date: Dec 2022 --> Apr 2021 | Trial primary completion date: Dec 2022 --> Apr 2021

We provide evidence implicating suppression of adaptive and innate immunity by adenosine as a mechanism for immune evasion by tumors. Inhibition of adenosine signaling through selective small molecule inhibition of AR using AZD4635 restores T cell function via an internal mechanism as well as tumor antigen cross-presentation by CD103 DCs resulting in antitumor immunity.

Our data suggest that the adenosine pathway can be successfully targeted in MM and blocking this pathway could be an alternative to PD1/PDL1 inhibition for MM and other hematological cancers. Inhibitors of the adenosine pathway are available. Some are in clinical trials and they could thus reach MM patients fairly rapidly.

For the CSPC/CRPC models, mice were orchidectomized and treated with apalutamide with or without AZD4635 for four or eight weeks to represent CSPC or CRPC phenotypes, respectively. Decreased expressions of immunosuppressive genes related to T regulatory cells (Ctla4, Il2ra, Itga2, Tigit, Foxp3) were noted in both CSPC and CRPC settings. Our findings show that targeting extracellular adenosine with AZD4635 is effective in a subset of mouse Pten-deficient tumors and provides evidence that suggests context-specific immune modulating activity by extracellular adenosine in prostate cancer.

P1, N=307, Recruiting, AstraZeneca | Trial completion date: Oct 2020 --> Mar 2021 | Trial primary completion date: Oct 2020 --> Mar 2021

P1b/2, N=98, Recruiting, MedImmune LLC | Trial completion date: Jul 2022 --> Oct 2022 | Trial primary completion date: Jul 2022 --> Oct 2022

P1b/2, N=98, Recruiting, MedImmune LLC | Trial completion date: Mar 2022 --> Jul 2022 | Trial primary completion date: Mar 2022 --> Jul 2022