Glycan Modulation of Insulin‐like Growth Factor‐1 Receptor

Abstract

The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) that plays critical roles in cancer. Microarray, computational, thermodynamic, and cellular imaging studies reveal that activation of IGF-1R by its cognate ligand IGF1 is inhibited by shorter, soluble heparan sulfate (HS) sequences (e.g., HS06), whereas longer polymeric chains do not inhibit the RTK, a phenomenon directly opposed to the traditional relationship known for GAG-protein systems. The inhibition arises from smaller oligosaccharides binding in a unique pocket in the IGF-1R ectodomain, which competes with the natural cognate ligand IGF1. This work presents a highly interesting observation on preferential and competing inhibition of IGF-1R by smaller sequences, whereas polysaccharides are devoid of this function. These insights will be of major value to glycobiologists and anti-cancer drug discoverers.

Designing Synthetic, Sulfated Glycosaminoglycan Mimetics That Are Orally Bioavailable and Exhibiting In Vivo Anticancer Activity

“…Further, HS06 was recently found to directly inhibit autoactivation of insulin-like growth factor–1 receptor (IGF-1R), a key cell surface receptor modulating the functions of CSC growth. In contrast, the polymer HS36 was devoid of such an inhibitory effect on IGF-1R . This chain length selectivity is unique and conveys the value in pursuing HS06 as a drug.…”

“… 46 More specifically, screening oligosaccharides of different chain lengths (HS02 → HS36) led to the observation that inhibition of colorectal spheroids was highest with HS hexasaccharides, and not as much with tetra- or octa-saccharides. Further, HS06 was recently found to directly inhibit autoactivation of insulin-like growth factor–1 receptor (IGF-1R), 47 a key cell surface receptor modulating the functions of CSC growth. In contrast, the polymer HS36 was devoid of such an inhibitory effect on IGF-1R.…”

“…In contrast, the polymer HS36 was devoid of such an inhibitory effect on IGF-1R. 47 This chain length selectivity is unique and conveys the value in pursuing HS06 as a drug. Unfortunately, HS06 is very expensive to produce, is not homogeneous, and also not orally bioavailable.…”

“… 22 It is likely that these molecules exhibit their effects by targeting a receptor tyrosine kinase, e.g. , IGF-1R, which is a known target of HS06, 47 the native GAG parent of G2.2. Such preferential targeting ability is infrequently observed among highly sulfated GAGs and could possibly arise due to the aromatic scaffold of G2.2 and its lipid analogues.…”

Non-Anticoagulant Activities of Low Molecular Weight Heparins—A Review

“…Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase that plays a key role in abnormal cell growth, tumor invasion, and metastasis and is involved in the development of breast, colorectal, lung, and liver cancers. Short-chain oligosaccharides (HS06) can enter a unique pocket in the IGF-1R ectodomain and compete with the natural cognate ligand IGF-1, thereby blocking the physiological processes mediated by IGF-1R and exerting anti-cancer effects [ 108 ]. Additional studies have shown that HS06 activates p38α/β mitogen-activated protein kinase, followed by inhibition of TCF4 signaling, ultimately inducing apoptosis in cancer stem cells [ 109 ].…”