G749 is a Fms-like tyrosine receptor kinase 3 (FLT3) inhibitor and a promising next-generation drug candidate for the treatment of relapsed and refractory acute myeloid leukemia (AML) patients with various FLT3-ITD/FLT3-TKD mutants that shows the ability to overcome drug resistance. It demonstrated potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. It also displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G749 yielded complete tumor regression and increased life span in animal models.

Crenolanib is an orally active, highly selective, small molecule, next generation inhibitor of platelet-derived growth factor receptor (PDGFR) tyrosine kinase. Crenolanib, manufactured by Arog Pharmaceuticals in Dallas, is taken orally with chemotherapy. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable, selective small molecule inhibitor of type III tyrosine kinases with nanomolar potencies against platelet-derived growth factor receptors (PDGFR) (isoforms PDGFRα and PDGFRβ) and Fms-related tyrosine kinase 3 (FLT3). Besides PDGFR and FLT3, crenolanib does not inhibit any other known receptor tyrosine kinase (RTK) (e.g. VEGFR and FGFR) or any other serine/threonine kinase (e.g., Abl, Raf) at clinically achievable concentrations. Preclinical trials have shown Crenolanib to be active in inhibiting both wild-type and mutant FLT3. Crenolanib is cytotoxic to the FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, with IC50s of 7 nM and 8 nM, respectively. In immunoblots, crenolanib inhibited phosphorylation of both the wild-type FLT3 receptor (in SEMK2 cells) and the FLT3/ITD receptor (in Molm14 cells) in culture medium with IC50s of 1-3 nM. Importantly, the IC50 of crenolanib against the D835Y mutated form of FLT3 was 8.8 nM in culture medium. Furthermore, crenolanib had cytotoxic activity against primary samples that were obtained from patients who had developed D835 mutations while receiving FLT3 TKIs. In vitro, the IC50 of crenolanib for inhibition of FLT3/ITD in plasma was found to be 34 nM, indicating a relatively low degree of plasma protein binding. From pharmacokinetic studies of crenolanib in solid tumor patients, steady state trough plasma levels of roughly 500 nM were found to be safe and tolerable, suggesting that crenolanib could potentially inhibit the target in vivo. Crenolanib has no significant activity against c-KIT, which may be an advantage in that myelosuppression can be avoided.1Furthermore, there was no evidence of QTc prolongation in patients treated with crenolanib. In summary, crenolanib offers a number of advantages over other FLT3 TKIs. Clinical trials of crenolanib in AML patients with FLT3 activating mutations are being planned.

Lestaurtinib (CEP-701, KT-5555) is an orally bio-available polyaromatic indolocarbazole alkaloid derived from K-252a. Lestaurtinib is a multi-targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.

CPI-0610 is a small molecule inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, with potential antineoplastic activity. Upon administration, the BET inhibitor CPI-0610 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. This disrupts chromatin remodeling and gene expression. Prevention of the expression of certain growth-promoting genes may lead to an inhibition of tumor cell growth. CPI-0610 is currently being evaluated in three Phase 1 clinical trials in the U.S.

Idasanutlin (RG-7388) is a second-generation, orally bioavailable, selective p53-MDM2 antagonist. MDM2 is an important negative regulator of the p 53 tumor suppressor and is expressed at high levels in a large proportion of acute myeloid leukemia (AML). Blocking the MDM2-p53 interaction stabilizes p53 and activates p-53 mediated cell death and inhibition cell growth. Idasanutlin is under clinical trial in phase III for treatment AML and in combinations with others drugs in phase I/II for treatment of multiple myeloma.

GSK2879552 – is an orally available, irreversible, inhibitor of lysine specific demethylase 1 (LSD1), with potential antineoplastic activity. Upon administration, GSK2879552 binds to and inhibits LSD1, a demethylase that suppresses the expression of target genes by converting the dimethylated form of lysine at position 4 of histone H3 (H3K4) to mono- and unmethylated H3K4. LSD1 inhibition enhances H3K4 methylation and increases the expression of tumor-suppressor genes. This may lead to an inhibition of cell growth in LSD1-overexpressing tumor cells. LSD1, overexpressed in certain tumor cells, plays a key role in tumor cell growth and survival. On October 2016 GlaxoSmithKline plans a phase I/II trial for Myelodysplastic syndromes (Monotherapy, Combination therapy, Second-line therapy or greater) in USA, Canada and Europe (PO) (NCT02929498).

R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM. R428 was originated in Rigel Pharmaceuticals and was licensed to BerGenBio, which initiated clinical trials for the treatment of non-small cell lung cancer, metastatic melanoma and acute myeloid leukaemia.

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.

p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. Based on X-ray cocrystal structures a model of AMG 232 bound to MDM2 was developed. The model shows that the m-chlorophenyl, the p-chlorophenyl, and C-linked isopropyl fragments of AMG 232 bind to the Leu 26(p53), Trp 23(p53), and Phe 19(p53) pockets of MDM2, respectively. The carboxylic acid forms a salt bridge with His 96 and the isopropyl sulfone forms a novel interaction with the glycine shelf region of MDM2. AMG 232 in phase II in combination with trametinib and dabrafenib in subjects with metastatic melanoma; in phase I for the treatment of solid tumors, multiple myeloma and Acute Myeloid Leukemia.

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.