PD-0325901 is an orally bioavailable inhibitor of mitogen-activated protein kinase kinases (MAPK/ERK kinases or MEK) with potential antineoplastic activity. MEK inhibitor PD325901, a derivative of MEK inhibitor CI-1040, selectively binds to and inhibits MEK, which may result in the inhibition of the phosphorylation and activation of MAPK/ERK and the inhibition of tumor cell proliferation. PD-0325901 is tested in clinical trials against non-small cell lung cancer, neurofibromatosis, melanoma and breast cancer.

X-396 (Ensartinib) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile. Ensartinib is currently in a global phase 3 trial in ALK positive non-small cell lung cancer (NSCLC) patients. The phase 1/2 clinical findings support the preclinical results that the use of ensartinib may result in favorable therapeutic outcomes in patients with ALK NSCLC, including patients with CNS metastases. In this study, ensartinib was generally well tolerated with the most common adverse event being a rash.

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.

Momelotinib (CYT387) is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases. Momelotinib is developing by Gilead Sciences for the oral treatment of pancreatic and non-small cell lung cancers, and myeloproliferative disorders (including myelofibrosis, essential thrombocythaemia and polycythaemia vera).

Capmatinib (INC280, INCB028060), is an orally bioavailable inhibitor of the proto-oncogene c-Met (hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. Novartis acquired Incyte's capmatinib, which is in Phase II clinical trial as monotherapy in patients with advanced hepatocellular carcinoma. Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.

Pralsetinib (GAVRETO™, Blueprint Medicines Corporation) is an orally-administered, next-generation, small-molecule selective rearranged during transfection (RET) inhibitor being developed for the treatment of various solid tumours. RET is a well described proto-oncogene present in multiple cancers including non-small cell lung cancer (NSCLC), papillary thyroid cancer, and medullary thyroid carcinoma. Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC50s) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1 at higher concentrations that were still clinically achievable at Cmax. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively. Pralsetinib is approved for the treatment of RET fusion-positive metastatic NSCLC. In the pivotal phase I/II ARROW trial, pralsetinib demonstrated rapid and durable anti-tumour activity in patients with advanced RET fusion-positive NSCLC who were previously treated with platinum-based chemotherapy or were treatment-naïve. Pralsetinib also showed clinical activity against intracranial metastases arising from NSCLC. Pralsetinib had a manageable tolerability profile, with the most common grade 3 treatment-related adverse events being neutropenia, hypertension, anaemia and decreased white blood cell count.

Lurbinectedin (PM-01183) - is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity. Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death. Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.

Selumetinib (AZD6244 or ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of Ras-Raf-mitogen-activated protein kinase kinase (MEK1/2). This inhibition can prevent ERK activation, disrupt downstream signal transduction, and inhibit cancer cell proliferation and survival. Selumetinib has shown tumour suppressive activity in multiple rodent models of human cancer including melanoma, pancreatic, colon, lung, and breast cancers. AstraZeneca is responsible for development and commercialization of selumetinib.

Lorlatinib is an investigational medicine that inhibits the anaplastic lymphoma kinase (ALK) and ROS1 proto-oncogene. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors. Lorlatinib has in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors. Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well. Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on a) the prior use of crizotinib and at least one other ALK inhibitor for metastatic disease, or b) the prior use of alectinib as the first ALK inhibitor therapy for metastatic disease, or c) the prior use of certinib as the first ALK inhibitor therapy for metastatic disease.

Dacomitinib is an oral, once-daily, pan-HER inhibitor. It is an irreversible inhibitor of HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases. Dacomtinib is being evaluated in phase 3 clinical trials against nonsmall-cell lung cancer. Direct comparison with erlotinib did not show superiority of dacomtinib, but subgroup analysis have demonstrated that subgroup with exon 19 deletion had favorable outcomes with dacomitinib. In addition to nonsmall-cell lung cancer dacomtinib is being evaluated against esophagus, head and neck and other neoplasms. Due to its ability to pass through blood-brain barrier, dacomitinib can be used to treat brain tumors.