Oncology Drugs- MOA

Cyclophosphamide

* Alkylating agent
* Alkylation of nucleophilic sites leading to cross-linking of DNA that’s hard to repair
* Acrolein is a toxic metabolite!

Cisplatin/Oxaplatin

* Platinum analogs
* Intra/interstrand cross-linking of cisplatin to DNA inhibits S phase replication and activate p53 tumor suppressor, activates pro-apoptotic proteins

Methotrexate

* Anti-metabolite, DHF analog
* Inhibition of purine & pyrimidine synthesis via competitive inhibition of DHFR
* Methotrexate becomes polyglutamate via FPGS, which is unregulated in tumor cells, and increases resident time in cells

5-FU

* Anti-metabolite
* deprive cell of thimidylate synthase, no TTP, and the cells starve
* Decreased DPYD function puts patient at risk of toxicity

Capecitabine

* Anti-metabolite
* Pro drug metabolized by carboxylesterase to 5-DFCR and then by cytidine deaminase to 5-DFUR
* 5-DFUR is metabolized within tumors to 5-FU by thymidine phosphorylase
* Targets cancer more preferentially than 5-FU

Cytarabine

* Anti-metabolite
* Deoxycytidine analog that works in S-phase, into ara-C that acts as a competitive inhibitor of DNA pol to inhibit DNA synthesis

Gemcitabine

* Anti-metabolite
* Deoxycytidine analog that works in S-phase, acts a competitive inhibitor of DNA polymerase to inhibit DNA synthesis

6-MP

* Purine antagonist
* 6-MP is converted into 6-TGNs via HPRT, 6-TGN is incorporated into DNA to arrest replication and trigger cell death
* Deficiency in TPMT increases toxicity risk

Vincristine/Vinblastine

* Mitotic inhibitor, vinca alkaloids
* Binds to beta-tublin to decrease microtubilin formation and carry out mitotic arrest

Paclitaxel/Docetaxel (& Abaxane)

* Mitotic inhibitor, taxane
* Binds to beta-tublin to decrease microtubilin formation and carry out mitotic arrest
* EXTENSIVE P450 METABOLISM

Ixabepilone/Eribulin

* Mitotic inhibitors
* Microtubule stabilizers
* Eribulin is a subunit sequestrant

Irinotecan

* Topoisomerase I inhibitor
* Irinotecan to SN-38 via carboxylesterase
* Maintain knotting of DNA, triggers apoptosis
* UGT1A1 deficiencies will increase toxicities

Etoposide

* Topoisomerase inhibitor
* Stabilize Topo II/DNA complex by preventing re-sealing of cleaved DNA and can interfere with replication and transcription
* Accumulation of DNA strand breaks

Doxorubicin/Daunorubicin

* Anthracyclines
* Intercalation into DNA helix, formation of oxygen radicals, inhibit DNA/RNA synthesis and inhibit Topo II

Bleomycin

* Anthracycline
* Iron binding, oxygen radical generation, DNA strand breaks, and chromosomal damage

Leuprolide and Goserelin

* GnRH receptor agonist
* Lowers testosterone after initial an initial up regulation to reduce stimulation of androgen-sensitive cancer cells, negative feedback loop

Degarelix

* GnRH receptor antagonist
* Lowers testosterone levels as a competitive inhibitor of the GnRH receptor to reduce stimulation of androgen sensitive cancer cells, trigger apoptosis

Flutamide and Bicalutamide

* Non-steroid competitive inhibitors of androgen receptor, block androgen receptor activity and inhibit transcription of androgen receptor genes
* Increase in estrogen levels = risk for gynecomastia

Enzalutamide

* Non-steroid competitive inhibitor of androgen receptor that reduces transcription of androgen receptor genes
* Second generation, higher affinity for AR than Bicalutamide
* DO NOT GIVE WITH CYP2C8 AND CYP3A4 INHIBITORS

Abiraterone

* Androgen synthesis inhibitor
* A progesterone derivative use to inhibit 17-alpha-hydroxylase irreversibly to reduce testosterone production
* Need to look at CYP17 activity

Anastrozole/Letrozole

* Estrogen synthesis inhibitor
* Non-steroidal aromatase inhibitors for the treatment of HR+ BC, decreased estrone/estradiol


* Bind reversibly to heme

Exemastane

* Estrogen synthesis inhibitor
* Steroidal aromatase inhibitor that irreversibly inactivates aromatase via reactive intermediate formation

Tamoxifen/Raloxifene

* SERMs
* Antagonists in breast tissue, to inhibit cell proliferation
* Agonist in uterine tissue, increased risk of uterine cancer

Megestrol

* Progesterone derivative that inhibits pituitary gonadotropin release

Fulvestrant

* SERDs
* Estrogen receptor antagonist, degradation of estrogen receptor by stimulating ubiquitnylation

Rituximab

* CD20 receptor antibody
* Chimeric mAb, triggers direct Ab-dependent cellular toxicity
* Risk of allergic response

Obinutuzumab/Ibritumomab

* CD20 receptor antibody
* 1: fully humanized mAb derivative of rituximab engineered to increase binding to effector cells
* 2: radiolabeled rituximab conjugate with higher complete remission, hard to use

Ibrutinib

* Non-receptor TKI, potent inhibitor of Btk, inhibits downstream PLC gamma
* Btk is unregulated in cancer & stimulates NF-KB, stimulates cell survival

Bevacizumab

* VEGF TKI
* Binds VEGFR to prevent VEGF binding, ultimately prevent angiogenesis

Sorafenib/Sunitinib

* Inhibitors of VEGFR, blocks ATP binding to kinase
* Short circuit internally

Cetuximab

* EGFR TKI
* Ab directed against EGFR to inhibit receptor signaling
* Chimeric precursor
* KRAS mutation means these drugs won’t work

Eriotinib (1st)/Afatinib (2nd)/Osimertinib (3rd)

* EGFR TKI’s
* Erotinib: reversible binder of EGFR
* Afatinib & osimertinib: irreversible EGFR binder

Lapatinib

* HER2 Signaling targets
* Reversible inhibitor of RTK, block HER2 and EGFR
* Blocks ATP binding site

Trastuzumab

* HER2 Signaling targets
* Bind receptor, trigger antibody cell toxicity, short circuit ability of receptors to dimerize and signal

Enhertu

* New HER2 signaling target
* New, Ab-drug conjugate

Imatinib

* Bcr-Abl TKI
* Binds ATP pocket in Bcr-abl where it stabilizes a catalytically inactive form of the enzyme, relatively specific
* Given chronically, T3151 mutants prevent imatinib binding
* Others: Ponatinib for T3151 mutations, nilotinib, dasitinib

Midostaurin

* FLT3 TKI
* Small molecule inhibitor of FLT3 that prevents dimerization of the receptor to silence downstream signaling associated with cancer cell proliferation

Bortezomib

* Proteasome inhibitor, serine protease
* Regulation of protein content by protease-mediated degradation of target proteins
* Generally prevent the degradation of pro-apoptotic proteins

Carfilzomib

* Proteasome inhibitor
* Irreversibly inhibits threonine protease activity of proteasome
* Regulation of protein content by protease-mediated degradation of target proteins
* Generally prevent the degradation of pro-apoptotic proteins

Ivosidenib

* Cell differentiation inducer
* Push cancer cells into differentiated cell
* Metabolized by CYP3A4, caution with inducers/inhibitors

Nivolumab

* Anti-PD 1 mAb
* Binds PD-1 instead of ligand binding & transmitting a signal to T-cells to prevent killing of cancer cell
* Enables T-cell to kill of the cancer cell

Pembrolizumab

* Anti PD1 mAb
* Breaks the connection between tumor cell and T-cell, allows T-cell to do its job in mediated tumor cell death

Durvalumab, Avelumab, Atezolizumab

* PD-L1 mAb
* Bind PD-L1 instead of PD-1, allow T-cell to do its job in mediated tumor cell death

CAR-T Therapy

* Based on engineering immune cells to recognize cancer cell specific antigens, targeting and destroying them
* Circumvent immunogenicity
* “Living drug”