Zotiraciclib

Zotiraciclib
Clinical data
Other names	TG02, SB1317
Routes of; administration	By mouth
ATC code	None;
Legal status
Legal status	Investigational;
Pharmacokinetic data
Protein binding	>99%
Metabolism	CYP3A4, CYP1A2
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;

Zotiraciclib (TG02) is a potent oral spectrum selective^{[clarification needed]}^[2] kinase inhibitor for the treatment of cancer. It was discovered in Singapore by S*BIO Pte Ltd and falls under the category of small molecule macrocycles. It crosses the blood brain barrier and acts by depleting Myc through the inhibition of cyclin-dependent kinase 9 (CDK9).^[3] 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.^[4]^[5] Myc overexpression is a known factor in many cancers, with 80 percent of glioblastomas characterized by this property.^[6] 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.^[7]^[8]

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.^[6]

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.^[9]

Zotiraciclib is also being explored for the treatment of DIPG, a rare pediatric cancer.^{[citation needed]}

References

^ ^a ^b Pasha MK, Jayaraman R, Reddy VP, Yeo P, Goh E, Williams A, et al. (March 2012). "Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor". Drug Metabolism Letters. 6 (1): 33–42. doi:10.2174/187231212800229336. PMID 22372550.
^ William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW (January 2012). "Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer". Journal of Medicinal Chemistry. 55 (1): 169–96. doi:10.1021/jm201112g. PMID 22148278.
^ Su YT, Chen R, Wang H, Song H, Zhang Q, Chen LY, et al. (March 2018). "Novel Targeting of Transcription and Metabolism in Glioblastoma". Clinical Cancer Research. 24 (5): 1124–1137. doi:10.1158/1078-0432.CCR-17-2032. PMC 8108069. 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.
^ ^a ^b Annibali D, Whitfield JR, Favuzzi E, Jauset T, Serrano E, Cuartas I, et al. (August 2014). "Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis". Nature Communications. 5 (4632): 4632. Bibcode:2014NatCo...5.4632A. doi:10.1038/ncomms5632. PMC 4143920. PMID 25130259.
^ "FDA grants orphan drug designation to zotiraciclib for the treatment of glioma". Center for Cancer Research. Cancer Research Center. 2020-01-09.
^ "EU/3/19/2202". European Medicines Agency. 2020-01-21.
^ Clinical trial number NCT02942264 for "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" at ClinicalTrials.gov

[Pasha-1] Pasha MK, Jayaraman R, Reddy VP, Yeo P, Goh E, Williams A, et al. (March 2012). "Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor". Drug Metabolism Letters. 6 (1): 33–42. doi:10.2174/187231212800229336. PMID 22372550.

[pmid22148278-2] William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW (January 2012). "Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer". Journal of Medicinal Chemistry. 55 (1): 169–96. doi:10.1021/jm201112g. PMID 22148278.

[3] Su YT, Chen R, Wang H, Song H, Zhang Q, Chen LY, et al. (March 2018). "Novel Targeting of Transcription and Metabolism in Glioblastoma". Clinical Cancer Research. 24 (5): 1124–1137. doi:10.1158/1078-0432.CCR-17-2032. PMC 8108069. PMID 29254993.

[4] 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.

[5] 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-6] Annibali D, Whitfield JR, Favuzzi E, Jauset T, Serrano E, Cuartas I, et al. (August 2014). "Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis". Nature Communications. 5 (4632): 4632. Bibcode:2014NatCo...5.4632A. doi:10.1038/ncomms5632. PMC 4143920. PMID 25130259.

[7] "FDA grants orphan drug designation to zotiraciclib for the treatment of glioma". Center for Cancer Research. Cancer Research Center. 2020-01-09.

[8] "EU/3/19/2202". European Medicines Agency. 2020-01-21.

[9] Clinical trial number NCT02942264 for "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" at ClinicalTrials.gov

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