A long‑term complete response to namodenoson in liver cancer with Child‑Pugh B cirrhosis: A case report

Abstract

Established treatments for advanced hepatocellular carcinoma (HCC) with Child-Pugh cirrhosis B (CPB, moderate hepatic dysfunction) are lacking. A recently published randomized phase 2 study in CPB HCC investigating the safety and efficacy of namodenoson (25 mg BID), an A3 adenosine-receptor agonist vs. placebo, suggested a favorable safety profile and a positive efficacy signal in patients with HCC with a CPB score of 7 (CPB7). The present study reports a 61-year-old woman with CPB7 HCC who received namodenoson for over 6 years through this study and its open-label extension. Computed tomography scans demonstrated partial and complete responses after 7 weeks and 4 years of treatment, respectively. Low albumin levels (31 g/l) and elevated baseline levels of alanine transaminase and aspartate aminotransferase (68 U/l and 44 U/l, respectively) were reported. After 4 weeks of treatment, these levels normalized and were stable for over 6 years. No treatment-emergent adverse events were noted. At the time of reporting, the response is ongoing as manifested by imaging studies and liver function evaluation.

2-Substituted (N)-Methanocarba A3 Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization

“…A 3 AR agonists have translational potential for ischemic and inflammatory conditions such as osteoporosis and psoriasis, pain, and cancer. − ,,,,, Here, we have expanded the range of active, but only moderately potent and selective A 3 AR agonists as in vivo probes of the actions of this receptor. These compounds clearly delineate the effects on receptor binding of simple aryl either directly attached to the adenine C2 position or through an ethynyl spacer.…”

“…1 H NMR (CD 3 OD, 400 MHz) δ 8.31 (brs, 2H), 8.10 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 5.21 (d, J = 6.4 Hz, 1H), 4.93 (s, 1H), 4.17 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 3.83 (brs, 2H), 2.83 (s, 3H), 2.17−2.14 (m, 1H), 1.84 (t, J = 5.2 Hz, 1H), 1. 40 (3aR,3bS,4aS,5R,5aS)-5-(6-(Ethylamino)-2-(4-methoxyphenyl)-9H-purin-9-yl)-N,2,2-trimethyltetrahydrocyclopropa [3,4]cyclopenta [1,2-d][1,3]dioxole-3b(3aH)-carboxamide (58). Compound 58 (77%) was synthesized from the 2-iodo derivative 48 following the mentioned general protocol for boronic acid coupling.…”

“…Compound 58 (77%) was synthesized from the 2-iodo derivative 48 following the mentioned general protocol for boronic acid coupling. 1 (3aR,3bS,4aS,5R,5aS)-5-(2-(5-Chlorothiophen-2-yl)-6-(ethylamino)-9H-purin-9-yl)-N,2,2-trimethyltetrahydrocyclopropa [3,4]cyclopenta [1,2-d] [1,3]dioxole-3b(3aH)-carboxamide (59). Compound 59 (82%) was synthesized from the 2iodo derivative 48 following the mentioned general protocol for boronic acid coupling.…”

“…The A 3 AR, a G protein-coupled receptor (GPCR) of Class A, has been modeled extensively using homology modeling and molecular dynamics (MD) simulation − prior to the very recent report of experimental structures. − We and others have investigated the structure–activity relationship (SAR) of adenosine-derived A 3 AR agonists, and recently structure-guided approaches have been used to arrive at highly selective agonists ,− , Two prototypical A 3 AR agonists 1a and 1b (Figure ) containing a 5′- N -methylcarboxamido-ribose moiety are in advanced clinical trials (Phases 2 and 3). ,− However, greater A 3 AR selectivity can be achieved by replacing the furanose ring of adenosine analogues with a North (N) methanocarba (bicyclo[3.1.0]hexyl) ring system. ,− , This ring system enforces a rigid conformation that approximates the receptor-preferred conformation, particularly in the A 3 AR case. The enhanced affinity is consistent with an entropic cost in the binding of the corresponding ribose analogue, which can attain either a (N) or South (S) conformation, either in solution or when receptor bound .…”

“…A 3 adenosine receptor (AR) agonists have potential applications in the treatment of chronic conditions. − These include inflammatory disorders, e.g. metabolic dysfunction-associated steatohepatitis (MASH, formerly known as NASH, a type of nonalcoholic fatty liver disease (NAFLD)), and the autoimmune skin disease psoriasis, stroke and traumatic brain injury and cancer (hepatocellular and pancreatic), − which are the subject of current clinical trials.…”