Alvocidib (also known as Flavopiridol or HMR-1275) is a flavonoid alkaloid CDK9 kinase inhibitor under clinical development for the treatment of acute myeloid leukemia, by Tolero Pharmaceuticals, Inc. As a broad spectrum CDK inhibitor, Alvocidib can inhibit cell cycle progression in either G1 or G2 and induces G1 arrest in either MCF-7 or MDA-MB-468 cells by inhibition of the CDK4 or CDK2 kinase activity. Alvocidib exhibits potent cytotoxicity against a wide variety of tumor cell lines (LNCAP, HCT116, A2780, K562, PC3, and Mia PaCa-2) with IC50 values ranging from 16 nM for LNCAP to 130 nM for K562. Administration of Alvocidib at 7.5 mg/kg for 7 days displays slight antitumor activity against P388 murine leukemia, and active against the human A2780 ovarian carcinoma implanted sc in nude mice). Alvocidib treatment at 1-2.5 mg/kg for 10 days significantly suppresses collagen-induced arthritis in mice in a dose-dependent manner, by inhibiting synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII are maintained. Tolero Pharmaceuticals Inc. announced that the FDA has granted orphan drug designation for Alvocidib, its cyclin-dependent kinase small molecule inhibitor, for the treatment of patients with acute myeloid leukemia.

Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high-affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. However, the company discontinued development of valspodar in April 2001 following disappointing results reported from several multicentre phase III studies.

Poziotinib is an inhibitor of EGFR tyrosine kinase family. The drug is being tested in phase II of clinical trials for different cancers: breast cancer, lung adenocarcinoma, head and neck squamous cell carcinoma, HER-2 positive advanced gastric cancer (in combination with Paclitaxel and Trastuzumab).

Senexin B is a selective CDK8/CDK19 inhibitor developed by Senex Biotechnology Inc. Senexin B is an ATP pocket binder, with very high target selectivity as indicated by kinome profiling. CDK8/19 inhibition produces chemopotentiating, chemopreventive and anti-metastatic effects in different types of cancer.

LTX-315 is a cationic amphipathic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis. The oncolytic effect of LTX-315 involves a unique immunogenic cell death targeting the mitochondria with subsequent release of danger-associated molecular pattern molecules. This initial targeting of the mitochondria is followed by disintegration of other cytoplasmic organelles resulting ineffective release of additional danger signals and a broad repertoire of tumour antigens and finally lysis of plasma membrane (necrosis). Preclinical and clinical studies have demonstrated LTX-315`s unique ability to reshape the tumour microenvironment by inducing the effective release of danger signals, chemokines and a broad repertoire of tumour antigens. These properties of LTX-315 results in enhanced infiltration of activated CD 8 T cells and Th1 responses. This ability to convert non-T cell inflamed tumours to T cell inflamed tumours makes LTX-315 an ideal combination partner with other types of immunotherapy, including immune checkpoint inhibitors/agonists, vaccines, and T cell-based therapies. Both preclinical and clinical studies have confirmed LTX-315s ability to induce a systemic anticancer immune response when injected locally into tumours resulting in complete or partial regression of injected and non-injected tumours (i.e. abscopal effect). Preclinical studies have demonstrated strong synergy with immune-checkpoint blockade which have given the scientific rationale for initiating combinations studies with Ipilimumab and Pembrolizumab in melanoma and TNB cancer patients respectively. Phase Ib study combining LTX-315 with ipilimumab (anti-CTLA4) in malignant melanoma patients, as well as LTX-315 with pembrolizumab (anti-PD-1) in metastatic breast cancer patients, is ongoing.

OTS-167 is a maternal embryonic leucine zipper kinase (MELK) inhibitor which demonstrated antitumor properties in laboratory tests. It is being developed as an anti-cancer drug. The compound has been shown to suppress the growth of breast, lung, pancreatic and prostate cancer cells that express high levels of the MELK protein. OTS167 reached phase II clinical trials in patients with AML, ALL, advanced MDSs, advanced MPNs, or advanced CML and phase I in patients with breast cancer.

BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. Bristol-Myers Squibb was developing BMS 690514, as an oral treatment for cancer. BMS-690514 had being in phase II for the treatment of breast cancer; non-small cell lung cancer, but later these studies were discontinued.

SU-14813 is an oral, multitargeted tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), KIT, and fms-like tyrosine kinase 3 (FLT-3). SU-14813 was developed as a next-generation TKI agent following sunitinib (SU-11248) designed to demonstrate optimized pharmacokinetic (PK) and tolerability profiles. SU14813 demonstrated broad and potent antitumor activity equivalent to that of sunitinib, which resulted in tumor regression, growth arrest, growth delay, and prolonged survival in established xenograft cancer models in mice. A phase II trial of SU-14813 in patients with breast cancer was completed. However, according to the Pfizer pipeline development has been discontinued.

CUDC-907 is a small molecule inhibitor of histone deacetylase and PI3 kinase developed by Curis. It is investigated in clinical trials for the treatment of relapsed or refractory lymphomas, thyroid cancer, multiple myeloma, breast cancer and other malignancies.

LY2606368 (Prexasertib) is a small-molecule Chk-1 inhibitors invented by Array and being developed by Eli Lilly and Company. Lilly is responsible for all clinical development and commercialization activities. LY2606368 is advancing in Phase 2 clinical trials for cancer. Prexasertib preferentially binds to and inhibits CHK1 and, to a lesser extent, inhibits CHK2. Chk-1 is a protein kinase that regulates the tumor cell's response to DNA damage often caused by treatment with chemotherapy. In response to DNA damage, Chk-1 blocks cell cycle progression in order to allow for repair of damaged DNA, thereby limiting the efficacy of chemotherapeutic agents. Inhibiting Chk-1 in combination with chemotherapy can enhance tumor cell death by preventing these cells from recovering from DNA damage.