Bafetinib

Last updated
Bafetinib
Bafetinib.svg
Clinical data
Other namesNS-187, INNO-406
Legal status
Legal status
  • Investigational
Identifiers
  • 4-[[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C30H31F3N8O
Molar mass 576.628 g·mol−1
3D model (JSmol)
  • CC1=C(C=C(C=C1)NC(=O)C2=CC(=C(C=C2)CN3CC[C@@H](C3)N(C)C)C(F)(F)F)NC4=NC=CC(=N4)C5=CN=CN=C5
  • InChI=1S/C30H31F3N8O/c1-19-4-7-23(13-27(19)39-29-36-10-8-26(38-29)22-14-34-18-35-15-22)37-28(42)20-5-6-21(25(12-20)30(31,32)33)16-41-11-9-24(17-41)40(2)3/h4-8,10,12-15,18,24H,9,11,16-17H2,1-3H3,(H,37,42)(H,36,38,39)/t24-/m0/s1
  • Key:ZGBAJMQHJDFTQJ-DEOSSOPVSA-N

Bafetinib (NS-187) is an experimental cancer drug developed by Nippon Shinyaku and licensed to CytRx. It is an inhibitor of Lyn and Bcr-Abl. [1] It reached phase II clinical trials in 2010.

Contents

Development

Imatinib was the first Bcr-Abl tyrosine-kinase inhibitor and was highly successful in treatment of chronic myelogenous leukemia, which had previous had no effective treatment. With the emerging resistance to imatinib treatment, alternative treatment was highly sought after. Bafetinib was created as an attempt for a more potent drug than imatinib, with efficacy against various point mutations in the Bcr-Abl kinase, with fewer adverse effects and with narrower kinase spectra, namely just Lyn and Bcr-Abl. [2] In the search for a substance that fit the criteria mentioned, the crystal structure of imatinib bound to Abl was examined. This revealed a hydrophobic pocket around the phenyl ring adjacent to the piperazinylmethyl group of imatinib. Attempts to utilize this pocket to increase efficacy led to the addition of various hydrophobic groups including single fluoro, bromo and chloro substituents. Finally a trifluoromethyl group at position 3 was found to give the best results, with approximately 36-fold improvement over imatinib. The addition of a hydrophobic group now needed to be countered to sustain the solubility of the substance. Closer examination of the crystal structure of imatinib-kinase complex revealed Tyr-236 was in close proximity to the pyridine ring of imatinib, suggesting there was little or no room for a larger group there. With that in mind a more hydrophilic pyrimidine ring was substituted for the pyridine, which was found to increase solubility while leaving efficacy the same or even slightly greater. Finally to improve the hydrogen bonding of the piperazine ring of imatinib with Ile-360 and His-361, pyrrolidine and azetidine derivatives were introduced. The most promising substance from these final modifications was labeled NS-187. [3]

The FDA granted NS-187 orphan drug status in 2007 for the treatment of chronic myeloid leukemia. [1]

Binding

Bafetinib in its binding site Bafetinib in binding site.PNG
Bafetinib in its binding site

Due to the structural similarities of imatinib and bafetinib, their binding to Bcr-Abl is also quite similar. The only notable difference comes from the hydrophobic interaction between the trifluoromethyl group and the hydrophobic pocket created by Ile-293, Leu-298, Leu-354, and Val-379. This group can also be linked to bafetinib's specificity for Lyn, as the binding site there is almost identical to that on Bcr-Abl. [4]

Bafetinib is effective both against most imatinib resistant mutations (not including T315I) and some dasatinib resistant mutations. Bafetinib also has more affinity for Bcr-Abl than nilotinib (but less than dasatinib) but only targets Bcr-Abl and Src family kinases Lck and Lyn; with unrivalled specificity which suggests the probability of fewer adverse effects. [5]

Clinical trials

Bafetinib was in phase II clinical trials for treatment of leukemia in 2010. [6] [7]

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Philadelphia chromosome</span> Genetic abnormality in leukemia cancer cells

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

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

Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

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

Nilotinib, sold under the brand name Tasigna marketed worldwide by Novartis, is a medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to imatinib. It is taken by mouth.

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

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth.

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

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

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

Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

<span class="mw-page-title-main">Nicholas Lydon</span> British biochemist

Nicholas B. Lydon FRS is a British scientist and entrepreneur. In 2009, he was awarded the Lasker Clinical Award and in 2012 the Japan Prize for the development of Gleevec, also known as Imatinib, a selective BCR-ABL inhibitor for the treatment of chronic myeloid leukaemia (CML), which converted a fatal cancer into a manageable chronic condition.

<span class="mw-page-title-main">Tyrosine kinase inhibitor</span> Drug typically used in cancer treatment

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.

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

Midostaurin, sold under the brand name Rydapt & Tauritmo both by Novartis, is a multi-targeted protein kinase inhibitor that has been investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.

<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.

Atypical chronic myeloid leukemia (aCML) is a type of leukemia. It is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes.

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

Radotinib (INN; trade name Supect), and sometimes referred to by its investigational name IY5511, is a drug for the treatment of different types of cancer, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance of other Bcr-Abl tyrosine-kinase inhibitors, such as patients resistant or intolerant to imatinib.

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

Saracatinib (AZD-0530) is an experimental drug being developed by AstraZeneca. It acts as a dual kinase inhibitor, with selective actions as a Src inhibitor and a Bcr-Abl tyrosine-kinase inhibitor.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

<span class="mw-page-title-main">Cancer pharmacogenomics</span>

Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.

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

Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia. Asciminib is a protein kinase inhibitor.

References

  1. 1 2 "Bafetinib". AdisInsight. Springer Nature Switzerland AG.
  2. Kimura S, Naito H, Segawa H, Kuroda J, Yuasa T, Sato K, et al. (December 2005). "NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia". Blood. 106 (12): 3948–54. doi: 10.1182/blood-2005-06-2209 . PMID   16105974. S2CID   15211440.
  3. Asaki T, Sugiyama Y, Hamamoto T, Higashioka M, Umehara M, Naito H, Niwa T (March 2006). "Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors". Bioorganic & Medicinal Chemistry Letters. 16 (5): 1421–5. doi:10.1016/j.bmcl.2005.11.042. PMID   16332440.
  4. Horio T, Hamasaki T, Inoue T, Wakayama T, Itou S, Naito H, et al. (May 2007). "Structural factors contributing to the Abl/Lyn dual inhibitory activity of 3-substituted benzamide derivatives". Bioorganic & Medicinal Chemistry Letters. 17 (10): 2712–7. doi:10.1016/j.bmcl.2007.03.002. PMID   17376680.
  5. Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y, Maekawa T (June 2008). "Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines". Leukemia Research. 32 (6): 980–3. doi:10.1016/j.leukres.2007.11.008. PMID   18191450.
  6. Santos FP, Kantarjian H, Cortes J, Quintas-Cardama A (December 2010). "Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia". Current Opinion in Investigational Drugs. 11 (12): 1450–65. PMID   21154127.
  7. Clinical trial number NCT01144260 for "A Pilot Phase II Study of Bafetinib (INNO-406) as Treatment for Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia (B-CLL)" at ClinicalTrials.gov