AZD-5363, a novel pyrrolopyrimidine-derived compound, inhibits all AKT isoforms with a potency of <10nM, and inhibited phosphorylation of AKT substrates in cells with a potency of ~0.3 to 0.8µM. AZD5363 monotherapy inhibited the proliferation of 41/182 solid and hematologic tumour cell lines with a potency of <3µM and 25/182 with a potency of <1µM. By targeting AKT, the key node in the PIK3/AKT signaling network, AZD-5363 may be used as monotherapy or combination therapy for a variety of human cancers. There is significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD-5363, and between RAS mutations and resistance. In xenograft studies in vivo AZD-5363 significantly reduced phosphorylation of PRAS40, GSK3β and S6. Chronic oral dosing of AZD-5363 causes dose-dependent inhibition of the growth of xenografts derived from various tumor types and AZD-5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib and trastuzumab in breast cancer xenografts. Dose-response at oral doses of 50 to 150mg/kg twice daily continuous dosing and intermittent dosing in the range of 100 to 200mg/kg twice daily, 4 days on, 3 days off have led to efficacy. AZD-5363 is in phase II clinical studies for the treatment of breast cancer; gastric cancer; non-small cell lung cancer.

KD025 is an orally available, selective small molecule inhibitor of ROCK2 (Rho-associated coiled-coil kinase 2), a molecular target in multiple autoimmune, fibrotic and neurodegenerative diseases. KD025 is the only ROCK2-specific inhibitor in the clinical trials. KD025 down-regulates the IL-17 and IL-21 secretion in human PBMCs, and leads to down-regulation of STAT3 phosphorylation, IRF4, and RORγt expression in CD4+ T cells. Kadmon Pharmaceuticals initiated phase II clinical trials of KD025 for the treatment of Graft-versus-host disease; Idiopathic pulmonary fibrosis; Plaque psoriasis.

AR-13503 is an active metabolite of Netarsudil

SAR407899 is a potent, ATP-competitive Rho kinase inhibitor. It antihypertensive action in animals. Sanofi is developing SAR 407899 for the treatment of microvascular angina (Syndrome X). It was previously being developed in clinical trials for the treatment of diabetic neuropathies, diabetic nephropathies, erectile dysfunction, pulmonary hypertension, hypertension and kidney disorders, but development was discontinued for those indications.

AT13148, being developed by Astex Pharmaceuticals and its collaborators, is an orally active small molecule inhibitor of Rho activated kinases (ROCK) 1 and 2 and of protein kinase (PK) A and is currently in phase 1 clinical studies under Cancer Research UK’s Clinical Development Program (CDP). AT13148 is currently being tested in a phase 1 clinical trial in patients with advanced solid tumors.

LX-7101 (Lexicon Pharmaceuticals) was advanced to Phase-I clinical trials for treatment open-angle glaucoma or ocular hypertension. This drug is a potent inhibitor of LIM-kinase 2 (LIMK2) kinase and inhibits to less extent LIMK1 and Rho-associated protein kinase 2 (ROCK2).

RKI 1447 is a potent and selective ROCK inhibitor. It displays anti-invasive and antitumor activities in breast cancer cells. RKI-1447 can inhibit the proliferation, migration and invasion abilities of ovarian cancer cells. RKI 1447 exhibits cytotoxic and cytostatic effects on VHL-deficient clear cell renal cell carcinoma (CC-RCC), making them candidate novel therapeutics for CC-RCC. RKI-1447 significantly inhibited mammary tumor growth in animal models.