Savolitinib (AZD6094, HMPL-504) has been demonstrated to inhibit the growth of tumors in a series of preclinical disease models, selectively for those tumors with aberrant c-Met signaling. Phase I dose escalation studies were initiated in Australia and China in 2012 and 2013 respectively. Savolitinib has demonstrated good safety and tolerability and favorable pharmacokinetic properties in late stage cancer patients, and has shown encouraging anti-tumor activity in several tumor-types, in particular for metastatic Papillary Renal Cell Cancer (PRCC). Phase II, study designed to evaluate the efficacy and safety of savolitinib in patients with locally advanced or metastatic PRCC. Approximately 20 centers in the United States, Canada, and Europe will participate in the study. The primary objective of this study is to assess the anti-tumor activity in patients with PRCC as measured by overall response rate according to Response Evaluation Criteria in Solid Tumours (“RECIST”). The secondary objectives for this study are to: assess the progression free survival and duration of response in patients with PRCC according to RECIST; assess the safety and tolerability in the treatment of patients with PRCC; characterize the pharmacokinetics and pharmacodynamics of savolitinib and metabolites following administration to steady state after multiple dosing when given orally.

TAK-733 had been developed by Millennium Pharmaceuticals (subsidiary of Takeda) for the treatment of adult patients with advanced non-hematological malignancies. In 2015, Takeda discontinued this studies. TAK-733 is an inhibitor of MEK that exhibits anticancer chemotherapeutic activity. In tumor explant models, TAK-733 induces tumor regression. In colorectal cancer cells and melanoma cells, this compound suppresses cell growth. Additionally, TAK-733 decreases tumor growth and weight in animal models of lung cancer and melanoma.

G-0853 (also GDC-0853, or Fenebrutinib) is a potent, selective, orally administered, and noncovalent Bruton's tyrosine kinase (Btk) inhibitor currently in clinical development. Upon administration, G-0853 inhibits the activity of Btk and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and Btk-mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK is overexpressed in B-cell malignancies, and plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival. G-0853 suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. G-0853 demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria.

EW-7197 is an orally bioavailable inhibitor of the serine/threonine kinase, transforming growth factor (TGF)-beta receptor type 1 (TGFBR1), also known as activin receptor-like kinase 5 (ALK5), with potential antineoplastic activity. EW-7197 is in phase I clinical trials for the treatment of solid tumors. Also, EW-7197 has a strong potential as an anti-fibrosis therapeutic agent.

Solcitinib (also known as GSK2586184 or GLPG0778) is a selective Janus kinase 1 (JAK1) inhibitor, for the treatment of psoriasis, lupus, and ulcerative colitis. Galapagos NV's collaboration with GlaxoSmithKline has hit a roadblock. It was reported that its Big Pharma partner had hit the brakes on a Phase II study of GSK2586184 for lupus after a first look at the data failed to demonstrate a positive effect. And an exploratory Phase I/II of the same drug for ulcerative colitis was put on hold as investigators review the program.

Novartis Oncology (previously Novartis) is developing nazartinib (formerly EGF 816), a third generation mutant-selective tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), for the treatment of solid malignancies, with a focus on non-small cell lung cancer. Nazartinib is a covalent mutant-selective EGFR inhibitor, with Ki and Kinact of 31 nM and 0.222 min−1 on EGFR(L858R/790M) mutant, respectively. Upon oral administration, nazartinib covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. EGF816 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors. As this agent is selective towards mutant forms of EGFR, its toxicity profile may be reduced as compared to non-selective EGFR inhibitors which also inhibit wild-type EGFR.

CP 724714 is an orally bioavailable, quinazoline-based, selective small molecule inhibitor of the HER2/erbB2 receptor tyrosine kinase. The compound could have particular potential in the treatment of women with metastatic breast cancer, of which 25-30% over express HER2/erbB2. CP 724714 was in preclinical development with Pfizer.

BVD-523 potently and selectively inhibits ERK1 and ERK2 kinases in a reversible, ATP-competitive fashion. Consistent with its mechanism of action, BVD-523 inhibits signal transduction, cell proliferation, and cell survival, most potently in cell lines bearing mutations that activate MAPK pathway signaling. Similarly, single-agent BVD-523 inhibits tumor growth in vivo in BRAF-mutant melanoma and colorectal xenografts as well as in KRAS-mutant colorectal and pancreatic models. BioMed Valley Discoveries is developing ulixertinib, a potent and selective small molecule inhibitor of ERK 1 and 2 kinases, as an oral treatment for cancers harbouring mutations in the MAPK signaling pathway. Phase I/II development of the drug for advanced cancers including, acute myeloid leukaemia and myelodysplastic syndromes is underway in the US. A phase I trial is underway in the US for pancreatic cancer.

CEP-37440 is a potent ATP-competitive, highly kinase selective, and orally active inhibitor of FAK1 and anaplastic lymphoma kinase (ALK). In addition to a favorable metabolic stability and pharmacokinetic profile preclinically, CEP-37440 is also a brain penetrant. CEP-37440 was able to inhibit the proliferation of certain IBC cells by decreasing the levels of phospho-FAK1 (Tyr 397); none of the cells expressed ALK. Studies using IBC xenograft models showed that CEP-37440 also effectively reduces the growth of the primary tumor xenografts and inhibits the development of brain metastases in mice.

Naquotinib (ASP8273) is an orally available, irreversible, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Naquotinib was found by mass spectrometry to covalently bind to a mutant EGFR (L858R/ T790M) via cysteine residue 797 in the kinase domain of EGFR with long-lasting inhibition of EGFR phosphorylation for 24 h. In the NSCLC cell lines harboring the above EGFR mutations, Naquotinib had IC50 values of 8-33 nM toward EGFR mutants, more potently than that of WT EGFR (IC50 value of 230 nM). In mouse xenograft models, Naquotinib induced complete regression of the tumors after 14 days of treatment. ASP8273 even showed activity in mutant EGFR cell line which is resistant to other EGFR TKIs. Naquotinib is in phase III clinical trials for the oral treatment of EGFR mutated non-small cell lung cancer (NSCLC).