Putting the pieces together: How is the mitochondrial pathway of apoptosis regulated in cancer and chemotherapy?

Elkholi, Rana; Renault, Thibaud T; Serasinghe, Madhavika N; Chipuk, Jerry E

doi:10.1186/2049-3002-2-16

Cancer & Metabolism

Table 1 Drugs currently in clinical trials targeting tumor suppressor/oncogene pathways or proteins within the mitochondrial pathway of apoptosis

From: Putting the pieces together: How is the mitochondrial pathway of apoptosis regulated in cancer and chemotherapy?

	Target	Drug	Mechanism	Clinical trial
Tumor suppressors/oncogenes	p53	ADVEXIN (Ade5CMV-p53)¹	Gene therapy for introduction of wtp53	Phase III
	P13K	Idelalisib (GS-1101)²	Inhibitor of PI3Kδ	Phase II
		Buparlisib³	ATP competitive inhibitor of class I PI3K	Phase II
		SAR245408 (XL 147)⁴	ATP competitive inhibitor of class I PI3K	Phase I/II
	P13K/mTOR	BEZ235³	Dual kinase inhibitor to PI3K and mTOR	Phase II
		BGT226³	Dual kinase inhibitor to PI3K and mTOR	Phase I
		PF-04691502⁵	Dual kinase inhibitor to PI3K and mTOR	Phase I/II
		SAR245409⁶	Dual kinase inhibitor to PI3K and mTOR	Phase II
	AKT	Perifosine⁷	Inhibitor to AKT	Phase I/II
	Receptor tyrosine kinases (e.g., EGFR)	Iressa (Gefitinib)⁸	ATP competitive tyrosine kinase inhibitor	Phase I/II
		Tarceva (Erlotinib)⁹	ATP competitive EGFR inhibitor	Phase II/III
		Cetuximab¹⁰	Monoclonal-antibody against EGFR prevents receptor dimerization	Phase II/III
		Tykerb (Lapatinib)¹¹	Inhibitor to receptor phosphorylation	Phase I/II
		Vectibix (Panitumumab)¹²	Monoclonal antibody against EGFR inhibits receptor activation	Phase II
	RAS	Salirasib¹³	Blocks RAS membrane association	Phase II
		Sarasar (Lonafarnib)¹⁴	Inhibitor to farnesyl transferase	Phase II
		Zarnestra (Tipifarnib)¹⁵	Inhibitor to farnesyl transferase	Phase II/III
	BRAF^V600E	Zelboraf (Vemurafenib)⁹	ATP-competitive selective inhibitor	Phase II
	RAF	Nexavar (Sorafenib)¹⁶	Multi-kinase inhibitor	Phase II/III
	RAF	Tafinlar (Dabrafenib)¹¹	ATP competitive kinase inhibitor	Phase I/II
	MEK	Mekinist (Trametinib)¹¹	MEK inhibitor	Phase II/III
Mitochondrial pathway	Anti-apoptotic BCL-2 proteins	Navitoclax (ABT-263)¹⁷	Inhibits BCL-2, BCL-w, and BCL-xL	Phase I/II
		ABT-199¹⁷	Inhibits BCL-2	Phase I
		Gossypol(AT-101)¹⁸	Inhibits BCL-2, BCL-xL, MCL-1 and BCL-w	Phase I/II
		Obatoclax¹⁹	Inhibits BCL-2, BCL-xL, and MCL-1	Phase I/II
	XIAP	GEM640 (AEG35156)²⁰	Blocks expression of XIAP	Phase I/II
	IAPs	LCL-161³	Peptidomimetic of SMAC-inhibits IAPs	Phase I/II
	IAPs	Birinapant (TL32711)²¹	Peptidomimetic of SMAC-inhibits IAPs	Phase II

Records were obtained from the National Cancer Institute and NIH clinical trials databases (http://www.cancer.gov; https://clinicaltrials.gov).
¹Introgen Therapeutics, TX, USA, ²Gilead, CA, USA, ³Novartis, Basel, Switzerland, ⁴Exelixis, CA, USA, ⁵Pfizer, NY, USA, ⁶Sanofi, Paris, France, ⁷Aeterna Zentaris, Quebec, Canada, ⁸Astra Zeneca, London, UK, ⁹Genentech, CA, USA, ¹⁰Imclone Systems Inc., NY, USA, ¹¹GlaxoSmithKline, Middlesex, UK, ¹²Amgen, CA, USA, ¹³Concordia Pharmaceuticals, FL, USA, ¹⁴Merck, NJ, USA, ¹⁵Johnson & Johnson, NJ, USA, ¹⁶Onyx Pharmaceuticals, CA, USA, ¹⁷AbbVie, IL, USA, ¹⁸Ascenta Therapeutics, PA, USA, ¹⁹Gemin X Pharmaceuticals, Quebec, Canada, ²⁰Aegera Therapeutics, Quebec, Canada, ²¹TetraLogic Pharmaceuticals, PA, USA.

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ISSN: 2049-3002

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