Oncology Drugs- MOA

Cyclophosphamide

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”