Table 1.

List of the most important dual pathway inhibitors.

Inhibitor	Target	Mechanism and Outcomes	Adverse Effects	Ref
Dactolisib (BEZ235)	PI3K/mTOR	⇑ G1 phase cell-cycle arrest ⇓ Cyclin D1/D3 expression ⇑ Tumor cell apoptosis ⇓ Tumor cell growth ⇓ Tumor cell migration ⇓ Chemoresistance ⇓ Angiogenesis ⇓ IL-4, IL-6, STAT3 ⇑ PFS	Nausea Diarrhea Vomiting Gastrointestinal toxicity Stomatitis	[101,102,103,104,105]
Gedatolisib (PKI-587)	PI3K/mTOR	⇑ G0/G1 cell-cycle arrest ⇑ Tumor cell apoptosis ⇓ Tumor cell growth ⇓ Chemoresistance ⇓ Colony formation ⇑ PFS	Anorexia Nausea Mucositis Fatigue	[106,107,108,109]
Voxtalisib (SAR245409)	Class-I PI3Ks, mTORC1/ mTORC2	⇑ Tumor cell apoptosis ⇓ Tumor cell growth ⇓ Chemoresistance	Diarrhea Nausea Fatigue	[110,111]
Bimiralisib (PQR309)	Pan-class I PI3K/mTOR	⇑ HRK, YPEL3, and TP63 ⇓ HSPA8, HSPA1B, CCDC86, PAK1IP1, and MIR155HG ⇓ Tumor cell growth ⇑ Tumor cell apoptosis ⇓ Disease volume Cross the BBB ⇑ Drug delivery to the brain	Hyperglycemia Fatigue Nausea Constipation Diarrhea Rash Vomiting Anorexia	[112,113,114]
Paxalisib (GDC-0084)	PI3K/mTOR	⇓ Cell viability ⇓ The phosphorylation of AKT and p70 S6 kinase AKT, p85, and S6K1 ⇓ Tumor cell growth ⇑ Tumor cell apoptosis ⇑ Cell cycle arrest Cross the BBB ⇑ Drug delivery to the brain ⇓ DNA-PKcs	Rash Neutropenia Hyperglycemia	[115,116,117,118,119,120]
Omipalisib (GSK2126458)	PI3K/mTOR	⇓ Colony formation of cancer stem cells ⇑ Autophagic cell death ⇓ The phosphorylation of mTOR, AKT, 4E-BP1, and S6K ⇓ Tumor cell growth ⇑ Tumor cell apoptosis ⇑ G0/G1 cell cycle arrest ⇓ Amino acid metabolism ⇑ PHGDH, PSPH, PSAT1, MTHFD1/2, and SHMT1/2	-	[121,122,123]
SF1126	PI3K/mTOR BRD4	Binding to specific integrins in the TME ⇓ HIF-2α stabilization ⇓ Tumor cell growth ⇑ Tumor cell apoptosis ⇑ G0/G1 cell cycle arrest ⇓ Tumor cell migration ⇓ Angiogenesis	-	[124,125,126]
PF-04691502	PI3K/mTOR	⇑ Radiosensitivity of tumor cells ⇑ Effectiveness of chemotherapy ⇑ Tumor cell apoptosis ⇓ Tumor cell growth ⇓ Tumor cell migration ⇓ Expression of pAKT ⇑ G1 phase cell-cycle arrest ⇓ CXCL12-related cell recruitment and migration	-	[127,128,129,130]
Samotolisib (LY3023414)	PI3K/mTOR	⇑ Tumor cell apoptosis ⇓ Tumor cell growth ⇑ PFS	Fatigue Nausea Vomiting Diarrhea	[131,132,133,134]
PWT33597	PI3K/mTORC1 and mTORC2	⇓ Tumor growth ⇓ Tumor weight and size ⇑ Cleaved caspase 3	-	[135]
Apitolisib (GDC-0980)	PI3K/mTOR	⇑ Effects of cisplatin or gemcitabine ⇓ Tumor cell colony formation ⇑ Tumor cell apoptosis ⇓ Tumor cell growth and metastasis ⇓ PERK	Hyperglycemia Rash	[136,137]
AptCCN	Glycolysis & oxidative phosphorylation	⇑ Depletion of arginine ⇑ NO stress ⇓ Tumor growth	-	[138]
KPT-9274	NAMPT/p21 PAK4	⇓ NAD+/NADH ratio in cancer cells ⇓ Tumor growth ⇑ Antitumor immune responses ⇑ Tumor antigen presentation ⇑ IFN-α & IFN-γ	-	[139]
20e and 20k	PDK/LDHA	⇓ Lactate formation ⇑ Enhance oxygen consumption	-	[140]
3,5-diamino-1,2,4-triazole analogs	KDM1A/SMOX	⇓ demethylation of H3K4 and H3K9 ⇓ The condensation of chromatin ⇑ The transcription DNMT-1, p53, p21, GATA-1 & GATA-2 ⇑ Gene expression control ⇑ ROS ⇑ Cell cycle regulation ⇑ DNA structure maintenance	-	[141,142]

PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; STAT3, signal transducer and activator of transcription 3; PFS, progression-free survival; BBB, blood–brain barrier; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; HIF, hypoxia-inducible factor; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; PERK, protein kinase R (PKR)-like endoplasmic reticulum kinase; NO, nitric oxide; IFN, interferon; DNMT1, DNA-methyltransferase 1; ROS, reactive oxygen species.