Zotiraciclib

Zotiraciclib
Clinical data
ATC code	None;
Identifiers
	IUPAC name (16Z)-14-Methyl-20-oxa-5,7,14,27-tetraazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(27),3,5,8(26),9,11,16,21,23-decaene;
CAS Number	1204918-72-8;
PubChem CID	16739650;
ChemSpider	30689952;
UNII	40D08182TT;
KEGG	D11599;
ChEMBL	ChEMBL1944698;
CompTox Dashboard (EPA)	DTXSID601337151 ;
Chemical and physical data
Formula	C23H24N4O
Molar mass	372.472 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CN1C/C=C\CCOc2cccc(c2)-c3ccnc(n3)Nc4cccc(c4)C1;
	InChI InChI=1S/C23H24N4O/c1-27-13-3-2-4-14-28-21-10-6-8-19(16-21)22-11-12-24-23(26-22)25-20-9-5-7-18(15-20)17-27/h2-3,5-12,15-16H,4,13-14,17H2,1H3,(H,24,25,26)/b3-2-; Key:VXBAJLGYBMTJCY-IHWYPQMZSA-N;

Comment: A review is being requested at WikiProject Pharmacology. Robert McClenon (talk) 22:58, 21 January 2020 (UTC)

Zotiraciclib (TG02) is a potent oral kinase inhibitor for the treatment of cancer that crosses the blood brain barrier and acts by depleting Myc through the inhibition of cyclin-dependent kinase 9 (CDK9).^[1] It is one of a number of CDK inhibitors under investigation; others targeting CDK9 for the treatment of acute myeloid leukemia include alvocidib and atuveciclib.^[2]^[3]

Myc overexpression is a known factor in many cancers, with 80 percent of glioblastomas characterized by this property.^[4] Zotiraciclib has been granted orphan drug designation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of gliomas.^[5]^[6]

As of January 2020^[update], zotiraciclib is being evaluated by Adastra Pharmaceuticals in two separate Phase 1b clinical trials for the treatment of glioblastoma multiforme (GBM). Zotiracicib is also being developed as a potential treatment for diffuse intrinsic pontine glioma (DIPG), a rare pediatric cancer. Both forms of brain cancer are characterized by Myc overexpression.^[7]

Development

The first Phase 1b clinical trial of zotiraciclib in GBM, sponsored by the National Cancer Institute (NCI), is a multi-arm, dose-finding study examining zotiraciclib plus dose-dense or metronomic temozolomide (TMZ) in adults with recurrent anaplastic astrocytoma and GBM.^[8]

The second Phase 1b trial of zotiraciclib is being conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and is designed as a three-parallel cohort, open-labeled, non-randomized, multicenter study in elderly patients with IDH1R132H-non mutant and MGMT promoter-unmethylated anaplastic astrocytoma or glioblastoma.^[9]

Zotiraciclib is also being explored for the treatment of DIPG, a rare pediatric cancer.

References

^ Yu-Ting, Su (March 2018). "Novel Targeting of Transcription and Metabolism in Glioblastoma". Clinical Cancer Research. 24 (5). doi:10.1158/1078-0432.CCR-17-2032. PMID 29254993.
^ Blachly, JS; Byrd, JC; Grever, M (April 2016). "Cyclin-dependent kinase inhibitors for the treatment of chronic lymphocytic leukemia". Seminars in oncology. 43 (2): 265–73. doi:10.1053/j.seminoncol.2016.02.003. PMID 27040705.
^ Lyle, L; Daver, N (August 2018). "Current and emerging therapies for patients with acute myeloid leukemia: a focus on MCL-1 and the CDK9 pathway". The American journal of managed care. 24 (16 Suppl): S356 – S365. PMID 30132679.
^ Annibali, Daniela (August 18, 2014). "Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis". Nature Communications. 5 (4632). doi:10.1038/ncomms5632. PMID 25130259.
^ "FDA grants orphan drug designation to zotiraciclib for the treatment of glioma". NIH National Cancer Institute. Cancer Research Center.
^ "EU/3/19/2202". European Medicines Agency.
^ Annibali, Daniela (Aug 18, 2014). "Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis". Nature Communications. 5 (4632). doi:10.1038/ncomms5632. PMID 25130259.
^ "Zotiraciclib (TG02) Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of Zotiraciclib (TG02) Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma". ClinicalTrials.gov.
^ "Study of TG02 in Elderly Newly Diagnosed or Adult Relapsed Patients With Anaplastic Astrocytoma or Glioblastoma (STEAM)". ClinicalTrials.gov.

External links

Adastra Pharmaceuticals

[1] Yu-Ting, Su (March 2018). "Novel Targeting of Transcription and Metabolism in Glioblastoma". Clinical Cancer Research. 24 (5). doi:10.1158/1078-0432.CCR-17-2032. PMID 29254993.

[2] Blachly, JS; Byrd, JC; Grever, M (April 2016). "Cyclin-dependent kinase inhibitors for the treatment of chronic lymphocytic leukemia". Seminars in oncology. 43 (2): 265–73. doi:10.1053/j.seminoncol.2016.02.003. PMID 27040705.

[3] Lyle, L; Daver, N (August 2018). "Current and emerging therapies for patients with acute myeloid leukemia: a focus on MCL-1 and the CDK9 pathway". The American journal of managed care. 24 (16 Suppl): S356 – S365. PMID 30132679.

[4] Annibali, Daniela (August 18, 2014). "Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis". Nature Communications. 5 (4632). doi:10.1038/ncomms5632. PMID 25130259.

[5] "FDA grants orphan drug designation to zotiraciclib for the treatment of glioma". NIH National Cancer Institute. Cancer Research Center.

[6] "EU/3/19/2202". European Medicines Agency.

[7] Annibali, Daniela (Aug 18, 2014). "Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis". Nature Communications. 5 (4632). doi:10.1038/ncomms5632. PMID 25130259.

[8] "Zotiraciclib (TG02) Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of Zotiraciclib (TG02) Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma". ClinicalTrials.gov.

[9] "Study of TG02 in Elderly Newly Diagnosed or Adult Relapsed Patients With Anaplastic Astrocytoma or Glioblastoma (STEAM)". ClinicalTrials.gov.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]