AMG-925, a dual FLT3/CDK4 inhibitor, has been developed to overcome resistance to FLT3 inhibitors, which is a serious clinical issue in treating acute myelogenous leukemia (AML). AMG-925 inhibits FLT3, including many FLT3 mutants reported to date. AMG-925 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, AMG-925 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation. AMG-925 is in Phase I clinical trials for the treatment of Acute myeloid leukaemia.

RO4987655 is a highly selective non-competitive small molecule inhibitor of MEK. RO4987655 has a strong anti-proliferation efficacy in various tumor cells including COLO205, HT29, QG56, MIA and C32 with IC50 values of 0.86nM, 1.7nM, 9.5nM, 3.3nM and 8.4nM, respectively. In addition, RO4987655 is found to have antitumor activity in a wide range of human cancer xenograft models. In the HT-29 human colon cancer xenograft, RO4987655 shows a strong inhibition of pERK formation as well as tumor regression. RO4987655 shows clinical activity in both patients with BRAF wild-type melanoma and BRAF V600-mutated melanoma. It is also efficacious in patients with KRAS-mutated non-small cell lung cancer but not KRAS-mutated colorectal cancer.

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.

Chugai Pharma Europe is developing CH-5132799, a phosphatidylinositol-3-kinase (PI3K) inhibitor, for the treatment of solid tumours. CH-5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. CH-5132799 selectively inhibits class I PI3Ks, PI3Kα (IC50 = 0.014 uM ), PI3Kβ (IC50 = 0.12 uM ), PI3Kδ (IC50 = 0.50 uM ), PI3Kγ (IC50 = 0.036 uM ), but shows less inhibition of class II PI3Ks, class III PI3k and mTOR and also no inhibitory activity (IC50 > 10 uM) against 26 protein kinases. CH-5132799 exhibits more inhibitory activities against PI3Kα with oncogenic mutations E542K (IC50 = 6.7 nM), E545K (IC50 = 6.7 nM) and H1047R (IC50 = 5.6 nM) than wild-type PI3Kα. CH-5132799 treated breast cnacer KPL-4 cells, which harbor the PIK3CA mutation, phosphorylation of Akt and its direct substrates, PRAS40 and FoxO1/3a and phosphorylation of downstream factors, including S6K, S6 and 4E-BP1, are effectively suppressed. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH-5132799. CH-5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. CH-5132799 is in phase I study to evaluate safety, pharmacokinetics and activity of CH-5132799 administered orally as a single agent in patients with advanced solid tumors.

GSK-461364 is a potent, selective, reversible, ATP-competitive inhibitor of Plk1. GSK-461364 broadly inhibits cancer cell proliferation with differential survival outcome. GSK-461364 blocks cells in G2 and M phases of the cell cycle and causes M-phase caspase-3/caspase-7 activation. GSK-461364 is efficacious in xenograft tumor models. GlaxoSmithKline is developing GSK-461364 for the treatment of solid tumours and non-Hodgkin's lymphoma.

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.

SAR-405838 is an inhibitor of the interaction between the oncoprotein murine double minute 2 (MDM2) and p53. SAR-405838 was investigated in phase I clinical trials in patients with locally advanced/metastatic solid tumor with wild-type TP53 or with TP53 mutation prevalence below 40%. SAR-405838 had an acceptable safety profile with limited activity in patients with advanced solid tumors.

AZD-8186 is a potent and selective inhibitor of PI3Kβ and PI3Kδ with IC50 of 4 nM and 12 nM, respectively. AZD-8186 is currently in phase 1 clinical trials. Combination therapy using AZD-8186 with androgen deprivation results in long-lasting tumor regression, which persisted after treatment cessation.

Q203 (6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide) is an an imidazopyridine antitubercular compound. Q203 targets the cytochrome b subunit (QcrB) of the cytochrome bc1 complex. This complex is an essential component of the respiratory electron transport chain of ATP synthesis. Q203 inhibited the growth of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Q203 is a promising new clinical candidate for the treatment of tuberculosis.

GDC-0994 (RG7842) is a selective inhibitor of ERK1/2, also known as extracellular-signal-regulated kinases. Daily, oral dosing of GDC-0994 results in significant single-agent activity in multiple in vivo cancer models, including KRAS-mutant and BRAF-mutant human xenograft tumors in mice. GDC-0994 neither increases nor decreases phospho-ERK, suggesting that different ERK inhibitors have alternative mechanisms of action with respect to feedback signaling. GDC-0994 is currently advancing in a Phase 1 trial in patients with solid tumors.