Novel Apelin receptor antagonist

• Potent (𝛽-Arrestin KB = 0.28nM ) and selective Apelin receptor antagonist, water soluble, excellent PK (mouse)
• Structurally-enabled and extensively-elaborated, with well-understood SAR
• Demonstrated therapeutic potential in orthotopic models of glioblastoma
• Well tolerated in vivo (mouse), with in vitro and in vivo data packages available

Apelin is an endogenous peptide identified as a ligand of the G protein-coupled receptor APJ. The extensive tissue distribution of Apelin and its receptor suggests involvement in many physiological processes. It has also been shown to participate in pathological processes such as heart failure and cancer. 

Apelin receptor is over-expressed in a number of cancers including glioblastoma (GBM), cervical, renal, lung and liver cancer. In GBM, Apelin expression is driven by tissue hypoxia and is known to promote tumor growth by direct stimulation of the tumor cell migration and metastasis. 

There exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumour spheres, induce tumour growth, and have been implicated in radio- and chemo-resistance. Our lead compound, MM315, has been shown to disrupt sphere formation and migration in GBM cell lines.

MM315 is a potent competitive antagonist of the Apelin receptor, demonstrating a binding affinity of 2.4 nM (pA2=9.55 for 𝛽-Arrestin, pA2=8.48 for cAMP). MM315 shows in vivo efficacy in GBM models, significantly extending survival in intracranial orthotopically implanted mice, and it has potential for synergy with temozolomide and radiation therapy. 

Patents covering MM315 and a diverse series of linear analogues have been filed in CRUK’s name and are at national/regional phase.