Spebrutinib (CC-292, AVL-292) is a selective inhibitor of BTK that was under clinical development for the treatment of rheumatoid arthritis (phase II) and B-cell Lymphoma (phase I). The drug was discovered by Avila Therapeutics, but then acquired by Celgene. Spebrutinib covalently binds to Cys 481 in BTK, blocking the ATP-binding pocket of the enzyme. The drug is no longer in Celgene's pipeline and its development is supposed to be terminated.

Brostallicin is a DNA minor groove binder which has shown very promising preclinical activity against a variety of human tumors both in vitro and in vivo. Brostallicin shows potent in vitro cytotoxic activity against tumor cells with IC50 values in the low nanomolar range, circumvents resistance to alkylating agents and camptothecins. Brostallicin has broad antitumor activity in animal models. A clear therapeutic gain is observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin, doxorubicin, and taxotere.

8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action remains poorly understood, however, it is known that the drug inhibits RNA synthesis. It has significant cytotoxic activity against lymphoid and myeloid malignant cells. The nucleoside analog 8-Cl-Ado is phosphorylated into its cytotoxic triphosphate 8-Cl-ATP. The accumulation of the cytotoxic metabolite results in a parallel decrease of the ATP cellular pools. 8-Cl-Ado gets incorporated into RNA during transcription, hindering this process. In addition, this triphosphate inhibits ATP-dependent poly(A) tail synthesis, and, as a consequence, mRNA processing is inhibited, resulting in vitro cytotoxicity in several solid and hematological malignancies. This agent is currently in clinical trials for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia.

Combretastatin is a phenol derivative isolated from the bark of Combretum caffrum, commonly known as South African Bush Willow. Combretastatin is an effective antimitotic agent, and like colchicine, inhibited tubulin polymerization and stimulated tubulin-dependent GTP hydrolysis.

Onalespib (AT13387; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, l-lactic acid salt), is wholly owned by Astex, a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. As a targeted inhibitor of Hsp90, onalespib has the potential to control the proliferation of multiple solid tumors and hematological malignancies where uncontrolled cell growth is dependent on the interaction between Hsp90 and its client proteins. Astex is pursuing an approach based on the observation that addition of onalespib to a molecularly targeted agent may delay the emergence of resistance to the agent, and hence prolong the window of therapeutic benefit. Onalespib is currently being evaluated via a CRADA with the National Cancer Institute (NCI) in various tumor types, and in a Phase 1/2 clinical study in combination with AT7519, Astex CDK inhibitor.

8-Azaguanine is a purine analog which resembles guanine close enough to compete with it in the metabolism of living organisms. It has been widely studied and has shown to cause retardation of some malignant neoplasms when administered to tumors in animals. It has been used for the treatment of patients with leukemia.

Perfosfamide is the active metabolite of the nitrogen mustard cyclophosphamide with potent antineoplastic and immunosuppressive properties. Perfosfamide alkylates DNA, thereby inhibiting DNA replication and RNA and protein synthesis. The incubation of normal human marrow cells with perfosfamide has a toxic effect on granulocyte-macrophage progenitor cells that is dose as well as white blood cell concentration dependent. It is likely that this dependency of the perfosfamide stem cell effect is caused not only by the target white blood cell concentration but by the suspension’s total protein concentration. Autologous bone marrow transplantation with perfosfamide purging in patients with acute myeloid leukemia in second complete remission produced results similar to that reported with allogeneic bone marrow transplantation. Perfosfamide had been in phase III clinical trial for the treatment of acute myeloid leukemia. However, this development was discontinued.

Piritrexim is a synthetic antifolate agent with antiparasitic, antipsoriatic and antitumor properties. Piritrexim inhibits the enzyme dihydrofolate reductase, thereby disrupting folate metabolism and DNA synthesis and cell division. A theoretical advantage of piritrexim over trimetrexate is a lack of any known effects on histamine metabolism, which may lower the risk of hypersensitivity reactions. Piritrexim is a nonclassical antifolate for antitumor and parasitic chemotherapy that passively diffuses into cells and hence do not have to depend on folylpoly-gamma-glutamate synthetase or the reduced folate carrier. Because piritrexim is not a substrate for polyglutamation, the drug is not selectively retained within cells for prolonged periods. Piritrexim has a reliably high oral bioavailability of about 75%, which has led to its development as an oral lipophilic antifolate. Most commonly, it has been administered in oral daily doses of 75 to 150 mg bid or tid every 5 days, with cycles repeated every 3 weeks. Oral absorption is rapid, with peak plasma levels appearing at 1.5 hours after ingestion. Elimination occurs primarily via hepatic metabolism of the drug to active metabolites, and the terminal half-life of the parent compound is about 1.5 to 4.5 hours. Single-agent oral piritrexim has clinical activity in melanoma, urothelial cancers, and head and neck cancers. Tolerable combinations of piritrexim with cisplatin, fluorouracil, and leucovorin have been tested, with promising results achieved in head and neck cancer. An interesting attempt to alternate piritrexim with methotrexate did not have any greater activity than methotrexate alone.

Vinfosiltine (also known as S 12363) was developed as a vinca alkaloid derivative. It is known that vinca alkaloids are widely used in the medical treatment of breast cancer. Vinfosiltine participated in the phase II clinical trial to treat the patients with advanced breast cancer. The results have shown that the drug didn’t have significant single-agent activity. As a result, the development of vinfosiltine was discontinued.

Raluridine (also know as 935U83) is a nucleoside analog reverse transcriptase inhibitor patented by Wellcome Foundation Ltd. for the treatment of HIV infection. Raluridine has demonstrated selective anti-human immunodeficiency virus (HIV) activity in vitro and favorable safety profiles in monkeys and mice. When tested in phytohemagglutinin-stimulated normal human peripheral blood lymphocytes against fresh clinical isolates of HIV type 1 Raluridine inhibited virus growth with an average 50% inhibitory concentration of 1.8 microM. Importantly, Raluridine retained activity against HIV strains that were resistant to zidovudine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytosine. The anabolic profile of Raluridine was similar to that of zidovudine, and Raluridine triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. In clinical trials systemic exposure to Raluridine at levels exceeding its average in vitro antiretroviral 50%, inhibitory concentration (approximately 1.8 microM) can be achieved after a single oral dose.