Filanesib

Last updated
Filanesib
Filanesib.svg
Names
Preferred IUPAC name
(2S)-2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
Other names
ARRY-520
Identifiers
3D model (JSmol)
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C20H22F2N4O2S/c1-25(28-2)19(27)26-20(11-6-12-23,14-7-4-3-5-8-14)29-18(24-26)16-13-15(21)9-10-17(16)22/h3-5,7-10,13H,6,11-12,23H2,1-2H3/t20-/m0/s1
    Key: LLXISKGBWFTGEI-FQEVSTJZSA-N
  • CN(C(=O)N1[C@](SC(=N1)C2=C(C=CC(=C2)F)F)(CCCN)C3=CC=CC=C3)OC
Properties
C20H22F2N4O2S
Molar mass 420.48 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Filanesib (code name ARRY-520) is a kinesin spindle protein (KIF11) inhibitor which has recently been proposed as a cancer treatment, specifically for multiple myeloma.

History of research

In 2009, two in vitro studies on the effects of filanesib on either ovarian cancer cells or acute myeloid leukemia cells were published. The former reported that filanesib "...has similar anti-tumor activity in EOC [epithelial ovarian cancer] cells as that of paclitaxel. However, unlike paclitaxel, it does not induce these pro-tumor effects in Type I cells." The detrimental effects attributed to paclitaxel were alleged to be "...due to paclitaxel-induced enhancement of NF-κB and ERK activities, and cytokine production (e.g. IL-6), which promote chemoresistance and tumor progression." [1] The latter study also reported promising results, concluding that filanesib "...potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML [acute myeloid leukemia] progenitor cells." [2] However, a clinical trial published in 2012 on patients with advanced myeloid leukemias found that the drug exhibited a "relative lack of clinical activity"; the trial was therefore halted before it was scheduled to end. [3]

In June 2013, preliminary results from a trial of the drug were presented at a conference of the European Hematology Association in Stockholm. On October 31, 2013, it was reported that the company which developed the drug, Array BioPharma (based in Boulder, Colorado), was planning on launching a phase III clinical trial of the drug to treat multiple myeloma. The study began in mid-2014, and paired filanesib with the proteasome inhibitor carfilzomib in several hundred patients. The study's primary endpoint was progression-free survival (i.e. the time until the cancer recurs). [4] A previous trial had reported that 37% of patients receiving filanesib in conjunction with carfilzomib showed lower levels of paraprotein, also known as "M protein", whereas only 16% of controls (i.e. those receiving only carfilzomib) showed such a reduction. [5] In addition, a report by the International Myeloma Working Group concluded that filanesib was "effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients." [6] According to Jatin Shah, an assistant professor at University of Texas MD Anderson Cancer Center, the primary adverse effect of treatment with filanesib observed in trials conducted thus far is reversible neutropenia, [7] though it is possible that it may cause low blood cell counts as well. [4] Shah et al. have conducted a phase II study of filanesib both by itself, and in combination with dexamethasone, presented at the annual meeting of the American Society of Hematology. [8] In December 2013, further clinical trial results were presented, also at the annual meeting of the American Society of Hematology; the results concluded that 16 percent of patients who had received a median of six prior therapies responded to single-agent filanesib. [9] In the week after this presentation, Array BioPharma's stock fell by 16%. [10] In February 2014, a review was published by researchers from the University of Salamanca in Spain, which concluded that "...some of these novel agents [to treat multiple myeloma] seem promising, such as monoclonal antibodies (anti-CD38 — daratumumab or anti-CS1 — elotuzumab) or the kinesin protein inhibitor Arry-520." [11]

A 2016 phase 1 dose-escalation study found that the studied dosing regimen of filanesib combined with bortezomib and dexamethasone had a favorable safety profile. The same study reported that this combination of drugs "appears to have durable activity in patients with recurrent/refractory multiple myeloma." [12]

Related Research Articles

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include amyloidosis.

<span class="mw-page-title-main">Lenalidomide</span> Pair of enantiomers

Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is used after at least one other treatment and generally with dexamethasone. It is taken by mouth.

<span class="mw-page-title-main">Bortezomib</span> Chemical compound

Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is generally used together with other medications. It is given by injection.

<span class="mw-page-title-main">Proteasome inhibitor</span>

Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. They are being studied in the treatment of cancer; and three are approved for use in treating multiple myeloma.

<span class="mw-page-title-main">Plasma cell leukemia</span> Medical condition

Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia, multiple myeloma. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.

<span class="mw-page-title-main">Panobinostat</span> Chemical compound

Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor.

<span class="mw-page-title-main">Blastic plasmacytoid dendritic cell neoplasm</span> Medical condition

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy. It was initially regarded as a form of lymphocyte-derived cutaneous lymphoma and alternatively named CD4+CD56+ hematodermic tumor, blastic NK cell lymphoma, and agranular CD4+ NK cell leukemia. Later, however, the disease was determined to be a malignancy of plasmacytoid dendritic cells rather than lymphocytes and therefore termed blastic plasmacytoid dendritic cell neoplasm. In 2016, the World Health Organization designated BPDCN to be in its own separate category within the myeloid class of neoplasms. It is estimated that BPDCN constitutes 0.44% of all hematological malignancies.

<span class="mw-page-title-main">Carfilzomib</span> Chemical compound

Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.

<span class="mw-page-title-main">Obatoclax</span> Chemical compound

Obatoclax mesylate, also known as GX15-070, is an experimental drug for the treatment of various types of cancer. It was discovered by Gemin X, which was acquired by Cephalon, which has since been acquired by Teva Pharmaceuticals. Several Phase II clinical trials were completed that investigated use of Obatoclax in the treatment of leukemia, lymphoma, myelofibrosis, and mastocytosis.

<span class="mw-page-title-main">Ponatinib</span> Oral drug

Ponatinib, sold under the brand name Iclusig, is a medication developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor. Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.

<span class="mw-page-title-main">Daratumumab</span> Monoclonal antibody

Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.

<span class="mw-page-title-main">Quisinostat</span> Chemical compound

Quisinostat is an experimental drug candidate for the treatment of cancer. It is a "second generation" histone deacetylase inhibitor with antineoplastic activity. It is highly potent against class I and II HDACs.

<span class="mw-page-title-main">Immunomodulatory imide drug</span> Class of immunomodulatory drugs

Immunomodulatory imide drugs (IMiDs) are a class of immunomodulatory drugs containing an imide group. The IMiD class includes thalidomide and its analogues. These drugs may also be referred to as 'Cereblon modulators'. Cereblon (CRBN) is the protein targeted by this class of drugs.

<span class="mw-page-title-main">Sonidegib</span> Chemical compound

Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

<span class="mw-page-title-main">Melphalan flufenamide</span> Chemical compound

Melphalan flufenamide, sold under the brand names Pepaxto and Pepaxti, is an anticancer medication used to treat multiple myeloma.

<span class="mw-page-title-main">Gedatolisib</span> Chemical compound

Gedatolisib (PF-05212384) is an experimental drug for treatment of cancer in development by Celcuity, Inc. The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

Selective inhibitors of nuclear export are drugs that block exportin 1, a protein involved in transport from the cell nucleus to the cytoplasm. This causes cell cycle arrest and cell death by apoptosis. Thus, SINE compounds are of interest as anticancer drugs; several are in development, and one (selinexor) has been approved for treatment of multiple myeloma as a drug of last resort.

References

  1. ↑ Kim, Ki Hyung; Xie, Yanhua; Tytler, Ewan M.; Woessner, Richard; Mor, Gil; Alvero, Ayesha B. (2009). "KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells". Journal of Translational Medicine. 7 (1): 63. doi: 10.1186/1479-5876-7-63 . PMC   2719595 . PMID   19619321.
  2. ↑ Carter, B Z; Mak, D H; Woessner, R; Gross, S; Schober, W D; Estrov, Z; Kantarjian, H; Andreeff, M (21 May 2009). "Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells". Leukemia. 23 (10): 1755–1762. doi:10.1038/leu.2009.101. PMC   3593228 . PMID   19458629.
  3. ↑ Khoury, H. J.; Garcia-Manero, G.; Borthakur, G.; Kadia, T.; Foudray, M. C.; Arellano, M.; Langston, A.; Bethelmie-Bryan, B.; Rush, S.; Litwiler, K.; Karan, S.; Simmons, H.; Marcus, A. I.; Ptaszynski, M.; Kantarjian, H. (2012). "A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias". Cancer. 118 (14): 3556–3564. doi:10.1002/cncr.26664. PMC   4984525 . PMID   22139909.
  4. 1 2 Herper, Matthew (31 October 2013). "Array Biopharma Outlines Path To Market For New Myeloma Drug". Forbes . Retrieved 5 February 2014.
  5. ↑ Owens, B. (2013). "Kinesin inhibitor marches toward first-in-class pivotal trial". Nature Medicine. 19 (12): 1550. doi: 10.1038/nm1213-1550a . PMID   24309639.
  6. ↑ Ocio, E. M.; Richardson, P. G.; Rajkumar, S. V.; Palumbo, A.; Mateos, M. V.; Orlowski, R.; Kumar, S.; Usmani, S.; Roodman, D.; Niesvizky, R.; Einsele, H.; Anderson, K. C.; Dimopoulos, M. A.; Avet-Loiseau, H.; Mellqvist, U. H.; Turesson, I.; Merlini, G.; Schots, R.; McCarthy, P.; Bergsagel, L.; Chim, J.; Lahuerta, J. J.; Shah, J.; Reiman, A.; Mikhael, J.; Zweegman, S.; Lonial, S.; Comenzo, R.; Chng, W. J.; Moreau, P. (2013). "New drugs and novel mechanisms of action in multiple myeloma in 2013: A report from the international myeloma working group (imwG)". Leukemia. 28 (3): 525–542. doi:10.1038/leu.2013.350. PMC   4143389 . PMID   24253022.
  7. ↑ "Array BioPharma Announces Positive Interim Results From Combination Trial Of ARRY-520 With Kyprolis At The 2013 European Hematology Association Congress". The Denver Post . 17 June 2013. Retrieved 16 December 2013.
  8. ↑ Lee, H. C.; Shah, J. J.; Orlowski, R. Z. (2013). "Novel Approaches to Treatment of Double-Refractory Multiple Myeloma". American Society of Clinical Oncology Educational Book. 33: 302–306. doi:10.1200/EdBook_AM.2013.33.e302. PMC   3762449 . PMID   23714530.
  9. ↑ Filanesib (ARRY-520) Continues To Show Promise In Heavily Pretreated Multiple Myeloma Patients (ASH 2013)
  10. ↑ Speights, Keith (14 December 2013). "3 Horrendous Health-Care Stocks This Week". Fool.com . Retrieved 7 April 2014.
  11. ↑ Ocio, Enrique M; Mitsiades, Constantine S; Orlowski, Robert Z; Anderson, Kenneth C (February 2014). "Future agents and treatment directions in multiple myeloma". Expert Review of Hematology . 7 (1): 127–141. doi:10.1586/17474086.2014.858595. PMC   4157182 . PMID   24350987.
  12. ↑ Chari, A; Htut, M; Zonder, JA; Fay, JW; Jakubowiak, AJ; Levy, JB; Lau, K; Burt, SM; Tunquist, BJ; Hilder, BW; Rush, SA; Walker, DH; Ptaszynski, M; Kaufman, JL (15 November 2016). "A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma". Cancer. 122 (21): 3327–3335. doi:10.1002/cncr.30174. PMC   6857452 . PMID   27433944.
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