Emerging therapeutic opportunities for integrin inhibitors

Abstract

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.

Fig. 1. The integrin family and targeted therapies.

All 24 distinct integrin heterodimers, formed from one α-subunit and one β-subunit, are represented and grouped according to their broad classification by cognate ligand or cellular expression. Therapeutically targeted integrins are highlighted in blue along with the therapeutic areas that are of current interest. Additionally, a select number of therapies in development, and marketed or terminated drugs and their modalities, are shown. Arrows are intended to demonstrate which integrin targets are thought to be key and their purpose is not to capture all known integrin activities. See Tables for additional information. ^aApproved for ulcerative colitis and Crohn’s disease. ^bBeing investigated clinically for ulcerative colitis. ^cAlso approved for Crohn’s disease in the USA.

Fig. 2. Selected small molecules with parenteral properties that bind to RGD integrins.

The small molecules shown here have either been evaluated in the clinic or have been examined in preclinical models and are administered by a parenteral route with advantageous potency or selectivity profiles. The molecules are: 1 cilengitide, 2 tirofiban, 3 JSM-6427 (proposed structure); 4 risuteganib (Luminate), 5 GSK3008348, 6 αvβ6 integrin small-molecule inhibitor, 7 GLPG0187, 8 acyclic peptide selective for αvβ8, 9 αvβ1 integrin small-molecule inhibitor, 10 CWHM-12, 11 SF0166 (now OT-166), 12 RUC-4. RGD, Arg–Gly–Asp.

Fig. 3. Selected small molecules with oral properties that bind to RGD integrins.

The small molecules shown here have either been evaluated in the clinic or have been examined in preclinical models and are administered by a parenteral route with advantageous potency or selectivity profiles or are predicted to have these attributes based on their physicochemical properties. The molecules are: 13 MK-0429, 14 SB-273005, 15 PLN-74809 (proposed structure), 16 an example of the series from Bristol-Myers Squibb patent WO2019/094319, 17 an example of the series from St Louis University and Indalo Therapeutics patent WO2018/132268, 18 an example from GlaxoSmithKline’s patent WO2016/046226, 19 an example of the series from St Louis University patent WO2017/117538. RGD, Arg–Gly–Asp.