Delving into the Latest Updates on AZD-4635 with Synapse

This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arms (referred to as modules).
Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

Start Date29 Aug 2019

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-4635

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100 Translational Medicine associated with AZD-4635

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100 Patents (Medical) associated with AZD-4635

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19

Literatures (Medical) associated with AZD-4635

24 Jul 2025·JOURNAL OF MEDICINAL CHEMISTRY

Chirality-Guided Optimization of A_2A Adenosine Receptor Antagonists for Enhanced Metabolic Stability and Antitumor Efficacy

Article

Author: Liu, Shuhao ; Liu, Wenjiang ; Hu, Wenhao ; Ding, Wen ; Zhang, Xiaolei ; Shi, Taoda ; Zhao, Jingyu ; Zhang, Zhijing

Blockade of the A_2A adenosine receptor (A_2AAR) by small-molecule antagonists holds promise for enhancing the efficacy of immune checkpoint inhibitors such as PD-L1 antibodies. However, many A_2AAR antagonists suffer from limited clinical success due to poor metabolic stability. In this study, we introduce chirality into the A_2AAR antagonist scaffold to address this challenge. This approach led to the discovery of (S)-E8, a chiral compound with markedly improved binding affinity, cellular activity, and in vivo potency compared with AZD4635, a Phase II clinical candidate. In contrast, its enantiomer (R)-E8 displays rapid metabolism and low efficacy, highlighting the importance of stereochemistry for therapeutic performance. Mechanistic studies identified CYP1A2 as the primary enzyme driving the metabolic differences among the enantiomers. These findings underscore the value of chirality-guided design in optimizing drug-like properties and reveal CYP1A2's pivotal role in enantioselective metabolism, offering a promising direction for the development of next-generation A_2AAR antagonists.

10 Apr 2025·JOURNAL OF MEDICINAL CHEMISTRY

Development of CD73 Inhibitors in Tumor Immunotherapy and Opportunities in Imaging and Combination Therapy

Review

Author: Patel, Jimmy S. ; Liang, Steven H. ; Bi, Chunyang

CD73 is a member of the membrane-bound enucleotidase family, which catalyzes the extracellular hydrolysis of adenosine monophosphate (AMP) to produce anti-inflammatory and immunosuppressive adenosine. As a novel checkpoint protein, CD73 is overexpressed in the immune system of various tumors, where adenosine is abundantly enriched. A large number of monoclonal antibodies (mAbs), nucleotides, and non-nucleotides as potent CD73 inhibitors are being discovered, providing opportunities for novel tumor immunotherapy. Currently, 18 CD73 inhibitors are in clinical trials, showing promising results in combination therapy for various solid tumors. The development of CD73-specific companion positron emission tomography imaging ligands holds potential for facilitating diagnosis, patient selection, and treatment efficacy evaluation throughout the entire process of CD73-targeted therapeutic development.

01 Oct 2024·Drug Research

Interaction of Purine and its Derivatives with A1, A2-Adenosine Receptors and Vascular Endothelial Growth Factor Receptor-1 (Vegf-R1) as a Therapeutic Alternative to Treat Cancer

Article

Author: Rosas, Marcela ; Mateu, Virginia ; Figueroa, Lauro ; Alvarez, Magdalena ; Aguilar, Emilio ; Bonilla, Enrique

Abstract:

Background There are several studies that indicate that cancer development may be conditioned by the activation of some biological systems that involve the interaction of different biomolecules, such as adenosine and vascular endothelial growth factor. These biomolecules have been targeted of some drugs for treat of cancer; however, there is little information on the interaction of purine derivatives with adenosine and vascular endothelial growth factor receptor (VEGF-R1). Objective The aim of this research was to determine the possible interaction of purine (1) and their derivatives (2–31) with A1, A2-adenosine receptors, and VEGF-R1. Methods Theoretical interaction of purine and their derivatives with A1, A2-adenosine receptors and VEGF-R1 was carried out using the 5uen, 5mzj and 3hng proteins as theoretical tools. 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. Results The results showed differences in the number of aminoacid residues involved in the interaction of purine and their derivatives with 5uen, 5mzj and 3hng proteins compared with the 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 Conclusions 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.

9

News (Medical) associated with AZD-4635

12 Nov 2021

·endpts.com

AstraZeneca expects 'modest profitability' for next round of Covid-19 vaccine supply deals — and prunes pipeline in Q3 update

Having sent 1.5 billion Covid-19 vaccines around the world on a not-for-profit basis, AstraZeneca says it’s time to move into “modest profitability.” While the priority is to deliver all the “pandemic doses” — a total of 3 billion are set to be delivered by the end of the year — AstraZeneca expects to be taking new orders in Q4, leading to a blend in sales. “Don’t expect massive profitability, which is sometimes the case for other vaccine makers,” Ruud Dobber, head of the biopharmaceuticals business unit, told Endpoints News . Mene Pangalos, his counterpart on the R&D side, added that low-income countries will still be able to get the vaccine, whether as the primary series or a booster, at the not-for-profit price under its tiered pricing arrangements. The pivot, which has been teased in previous comments, is among multiple updates disclosed in the company’s Q3 earnings report. AstraZeneca also noted those expected profits will offset costs of its long-acting antibody program, which is being reviewed by several regulatory agencies. Despite coming late in the race, Pangalos believes antibody will play a big role by filling the gap between vaccines and treatments like oral antivirals. “Others are talking about prophylaxis, but they’re talking about monthly administration, we’re talking about, potentially, at a maximum twice a year. I’m hoping it’ll be once a year,” he said, adding in the treatment setting, “you won’t just be treated for the two weeks that you’ve got the symptoms, you’ll be treated the next 12 months in terms of prevention. I know what I would take.” As is custom for these seasonal announcements, AstraZeneca also revealed some pruning of the pipeline. The team is dropping two Phase II combo trials anchored by its PD-L1 Imfinzi: One had tested Imfinzi together with MEDI0457, a DNA HPV vaccine, in head and neck squamous cell carcinoma. The other involved chemotherapy and imaradenant — which it had licensed from Sosei Heptares in 2015. Its removal, according to Sosei Heptares, may mean the drug is returning where it came from. Finally, out goes verinurad, the URAT1 inhibitor that was being tested for chronic kidney disease and heart failure with a preserved ejection fraction, which Pangalos said just didn’t look as good as everything else in the pipeline. “Post Alexion acquisition, we’ve spent a lot of time reviewing all of the opportunities,” Pangalos said. “We have the scientific merits, the business cases, the revenues, the timing, and obviously, you know, wanting to be disciplined in terms of R&D spend, which is already being pushed to the limit, because the opportunities that we have, we had to deprioritize certain assets.” Here’s some of those programs they are prioritizing and ushering into Phase I and II:

VaccineAntibodyAcquisition

11 Feb 2021

·www.biospace.com

AstraZeneca Touts Profits While Slashing Programs

Rob Stothard/Getty Images In the waning weeks of the fourth quarter of the 2020 fiscal year, AstraZeneca terminated several clinical programs, including some oncology and heart-related studies, as well as one COVID-19 related trial. AstraZeneca CEO Pascal Soriot pictured above. (Rob Stothard/Getty Images) In the waning weeks of the fourth quarter of the 2020 fiscal year, AstraZeneca terminated several clinical programs , including some oncology and heart-related studies, as well as one COVID-19 related trial. This morning, the U.K. pharma giant announced its year-end financial results that showed a 10% increase in revenue. Chief Executive Officer Pascal Soriot touted the company’s year-long performance that was driven by pipeline achievements, the success of its COVID-19 vaccine developed with Oxford University and its year-end dive into rare diseases with the $39 billion acquisition of Alexion. In his comments about the full-year results, Soriot pointed to the continued success of branded products like Tagrisso and Farxiga, an SLG2 inhibitor. But, despite those successes, the company saw some failures, which led to the termination of some of the studies, including two with Farxiga, which has been approved to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors. Farxiga has also been approved as a monotherapy and as a combination treatment to improve blood sugar control in type 2 diabetes. Both of the culled Farxiga studies were for heart failure. AstraZeneca killed trials assessing the drug in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) for strategic purposes, the company said. During the fourth quarter, AstraZeneca also canceled five different cancer studies, all for safety and efficacy reasons. One of the studies was assessing the company’s PD-1 inhibitor Imfinzi with tremelimumab, an anti-CTLA4 antibody, as a first-line treatment for head and neck squamous cell carcinoma (HNSCC). Earlier this month, the company reported the Phase III KESTREL study did not meet the primary endpoint of improving overall survival in HNSCC patients whose tumors expressed high levels of PD-L1. Also, the combination of Imfinzi plus tremelimumab did not indicate an OS benefit in ‘all-comer’ patients, a secondary endpoint. Two of the oncology programs AstraZeneca halted were in prostate cancer. AstraZeneca halted a study of oleclumab and imaradenant for safety and efficacy reasons. A separate prostate cancer study with imaradenant as a standalone treatment was also canceled for safety and efficacy reasons. Another study terminated was an investigation of AZD9496 as a potential treatment for estrogen receptor-positive breast cancer. AZD9496 is a selective estrogen receptor degrader (SERD) administered orally. It is similar to an older AstraZeneca drug Faslodex, an injectable SERD that has been approved to treat hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, as well as for the treatment of HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. Another experimental treatment terminated in the fourth quarter is AZD5153 for solid tumors and hematological malignancies. AstraZeneca noted this study was terminated due to safety and efficacy. As expected, AstraZeneca also canceled a study assessing its BTK-inhibitor Calquence in COVID-19 patients following a trial failure. In November, the company reported that Calquence (acalabrutinib) failed to meet its primary endpoints in the Phase II CALAVI trials in hospitalized patients with respiratory symptoms of COVID-19.

Phase 2VaccinePhase 3Financial StatementDrug Approval

11 Feb 2021

·www.biospace.com

AstraZeneca Touts Profits While Slashing Programs

AstraZeneca CEO Pascal Soriot pictured above. (Rob Stothard/Getty Images) In the waning weeks of the fourth quarter of the 2020 fiscal year, AstraZeneca terminated several clinical programs, including some oncology and heart-related studies, as well as one COVID-19 related trial. This morning, the U.K. pharma giant announced its year-end financial results that showed a 10% increase in revenue. Chief Executive Officer Pascal Soriot touted the company’s year-long performance that was driven by pipeline achievements, the success of its COVID-19 vaccine developed with Oxford University and its year-end dive into rare diseases with the $39 billion acquisition of Alexion. In his comments about the full-year results, Soriot pointed to the continued success of branded products like Tagrisso and Farxiga, an SLG2 inhibitor. But, despite those successes, the company saw some failures, which led to the termination of some of the studies, including two with Farxiga, which has been approved to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors. Farxiga has also been approved as a monotherapy and as a combination treatment to improve blood sugar control in type 2 diabetes. Both of the culled Farxiga studies were for heart failure. AstraZeneca killed trials assessing the drug in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) for strategic purposes, the company said. During the fourth quarter, AstraZeneca also canceled five different cancer studies, all for safety and efficacy reasons. One of the studies was assessing the company’s PD-1 inhibitor Imfinzi with tremelimumab, an anti-CTLA4 antibody, as a first-line treatment for head and neck squamous cell carcinoma (HNSCC). Earlier this month, the company reported the Phase III KESTREL study did not meet the primary endpoint of improving overall survival in HNSCC patients whose tumors expressed high levels of PD-L1. Also, the combination of Imfinzi plus tremelimumab did not indicate an OS benefit in ‘all-comer’ patients, a secondary endpoint. Two of the oncology programs AstraZeneca halted were in prostate cancer. AstraZeneca halted a study of oleclumab and imaradenant for safety and efficacy reasons. A separate prostate cancer study with imaradenant as a standalone treatment was also canceled for safety and efficacy reasons. Another study terminated was an investigation of AZD9496 as a potential treatment for estrogen receptor-positive breast cancer. AZD9496 is a selective estrogen receptor degrader (SERD) administered orally. It is similar to an older AstraZeneca drug Faslodex, an injectable SERD that has been approved to treat hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, as well as for the treatment of HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. Another experimental treatment terminated in the fourth quarter is AZD5153 for solid tumors and hematological malignancies. AstraZeneca noted this study was terminated due to safety and efficacy. As expected, AstraZeneca also canceled a study assessing its BTK-inhibitor Calquence in COVID-19 patients following a trial failure. In November, the company reported that Calquence (acalabrutinib) failed to meet its primary endpoints in the Phase II CALAVI trials in hospitalized patients with respiratory symptoms of COVID-19. Most Read Today

Financial StatementAntibodyVaccineAcquisition

100 Deals associated with AZD-4635

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic castration-resistant prostate cancer	Phase 2	United States	AstraZeneca PLC	29 Aug 2019
metastatic non-small cell lung cancer	Phase 2	United States	AstraZeneca PLC	08 May 2018
metastatic non-small cell lung cancer	Phase 2	South Korea	AstraZeneca PLC	08 May 2018
Non-Small Cell Lung Cancer	Phase 2	United States	MedImmune LLC	08 May 2018
Non-Small Cell Lung Cancer	Phase 2	China	MedImmune LLC	08 May 2018
Non-Small Cell Lung Cancer	Phase 2	South Korea	MedImmune LLC	08 May 2018
Advanced Malignant Solid Neoplasm	Phase 1	United States	AstraZeneca PLC	17 Jun 2016
Castration-Resistant Prostatic Cancer	Phase 1	United States	AstraZeneca PLC	17 Jun 2016
Metastatic Colorectal Carcinoma	Phase 1	United States	AstraZeneca PLC	17 Jun 2016
Metastatic Prostate Carcinoma	Phase 1	United States	AstraZeneca PLC	17 Jun 2016

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Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03980821 (Pubmed \| Cancer Chemother Pharmacol) Manual	Phase 1	Advanced Malignant Solid Neoplasm adenosine A2A receptor	10	Imaradenant 50 mg QD	bxkubaknku(uvtpfjvmjs) = The most common adverse events were nausea, malaise, decreased appetite, and vomiting. qsdqxcmgxc (ionaxampzi ) View more	Positive	01 Apr 2024
NCT04089553 (Pubmed) Manual	Phase 2	Metastatic castration-resistant prostate cancer Third line	59	AZD4635 + durvalumab	xneshxbdpv(amopdpscsp) = dpwstohrvy oqtsaxbijl (bpljolfwpy ) View more	Negative	02 Mar 2024
				AZD4635 + oleclumab	apjwhxgmsc(grlnwocfzp) = dfytqqommv kfwcljugox (wyxzktuqvh ) View more
NCT04495179 (AARDVARC, CTgov)	Phase 2	Metastatic castration-resistant prostate cancer	30	AZD4635+Durvalumab (Arm A: AZD4635 + Durvalumab)	kvzufsomlt(ydbqcefwkq) = zlupjvgoem ibdqtldren (chgndeedkk, zktvrygzya - ugxdcyaoke) View more	-	09 Aug 2023
				Cabazitaxel+AZD4635+Durvalumab (Arm B: AZD4635 + Durvalumab + Cabazitaxel)	lwarbxpfwo(epmivsnoud) = uatyyuujiz jtvcdhxztv (zgpdgaratp, wfifykzytv - ticbkygvii) View more
NCT04089553 (AARDVARC, ASCO_GU2023) Manual	Phase 2	Metastatic castration-resistant prostate cancer	28	AZD4635+durvalumab+cabazitaxel	jihsttzose(ajdxdvavgd) = bnftsmuwvy mrvscgvusc (micqrutbjj, 4.2–NE) View more	Negative	21 Feb 2023
NCT04089553 (ESMO2022) Manual	Phase 2	Metastatic castration-resistant prostate cancer Third line adenosine gene signature	59	AZD4635 75 mg+Durvalumab 1500 mg	tuporqcvho(xrjanwtjri) = uqlgtnatdk radupxoewn (jixcejglvh ) View more	Negative	10 Sep 2022
				AZD4635 50 mg or 75 mg+Oleclumab 1500 mg	tuporqcvho(xrjanwtjri) = zybrwtmteo radupxoewn (jixcejglvh ) View more
NCT04089553 (AARDVARC, CTgov)	Phase 2	Metastatic castration-resistant prostate cancer	59	AZD4635+Durvalumab (Module 1 (AZD4635 75 mg + Durvalumab 1500 mg))	hsncslatjz = zoisscxbaz bindpikown (kuzszgemhh, vujemgjwyg - shgqktqgrq) View more	-	08 Jul 2022
				AZD4635+Oleclumab (Module 2 (AZD4635 50 / 75 mg + Oleclumab 1500 mg))	hsncslatjz = nyatlgnyhd bindpikown (kuzszgemhh, wjnskwxuiq - lukpgxdqpv) View more
NCT03710434 \| NCT02740985 (AACR2020)	Phase 1	Neoplasms	-	AZD4635 nanosuspension	kiscpumdis(nkghknwocs) = flcedivzgp pjfrdlnxlp (derveugifc ) View more	-	15 Aug 2020
				AZD4635 capsule formulation	igbckqnzue(lvnbozcdot) = fwbdqqygkj njnrnyolqi (cfrgxxlkfl ) View more
NCT02740985 (ASCO 12020 \| ASCO 22020) Manual	Phase 1	Castration-Resistant Prostatic Cancer	94	AZD4635	lowwehjqkb(dcmrqhvqga) = nausea, vomiting, fatigue, decreased appetite, dizziness, and diarrhea. gxxalwhmws (erqhyuouvn ) View more	Positive	29 May 2020
				Durvalumab+AZD4635