Drug Bank

Chlorambucil

DNA Alkylator

Aromatic mustard which is react with DNA much slower and can be administered orally

less electrophillic

Melphalan

An attempt to enhance the cellular uptake of Chlorambucil via the phenylalanine-transport mechanism by adding a phenylalanine to the structure

Temozolomide

Transporter for a Tetrazinone ring

it breaks down via hydrolysis until we are left with methyldiazonium ions

the methyldiazonium ions are responsible for methylating DNA

Mitomycin

• N² and N⁷ atoms of guanine in the minor groove of DNA are primary alkylation sites

• Has to react with two guanines from opposite strands and cross links which prevents strand separation, blocking replication and transcription.

• Used in MRSA

PBDs

Pyrrolo benzodiazepines - antitumour antibiotics

• acts as a defence mechanism

• “suicide bomber” molecule - it is dangerous to itself and acts as a final measure.

• Imine is active substance and causes SN2 substitution

• PBDs bind covalently to the minor groove of DNA which blocks transcription factors and RNA polymerase from accessing the DNA.

Loncastuximab

anti-CD19 antibody-drug conjugate which consists. of the antiCD19 antibody and cytotoxic PBD dimer alkylating agent SG3199

• binds to the cd19 antigen on the tumour cell surface

• It is internalised and the PBD dimer is released

• binds to the minor groove of the cell DNA and forms potent cytotoxic DNA cross-links

Bleomycins

DNA cleaving agents

used clinically in combination chemotherapy against lymphomas, squamous-cell carcinomas and germ-cell tumours.

They induce DNA strand breaks by causing oxidative damage “cutting” DNA on one strand and swings around and rearranged itself to cut DNA strand below to completely separate the DNA

Platinum Drugs

• Comes with two clorine molecules

• dissolve in water which displaces the clorine

• water is then displaced by DNA causing intrastrand crosslink

Anthracyclines

TOP 2 inhibitors

• insert themselves between DNA base pairs

• stabilises the Top2-DNA cleavage complex preventing the resealing of the DNA after it breaks

• the accumulation of the ds breaks cause genomic stability which lead to cell death

Doxorubin

Interact with and stabilise top II and SN-38 interacts with top I dna complexes respectively to produce a "clearable complex” resulting in DNA strand breakage

Pluramycin

binds peripherally to the TATA-binding protein (TBP)

this allows for targeted alkylation at that single point of the DNA whereas when it is binded to the DNA strand, it alkylates everywhere

CPT

• anti cancer activity

• TOP1 inhibitor

SN-38

active metabolite of Irinotecan (CPT-11)

a topoisomerase I inhibitor used in chemotherapy

Telmestatin

inhibits telomerase

can take very long time due to length of telomers so lag of med to work can take weeks

Apalutamide

2nd gen anti-androgen

used for non-metastatic castrate resistant prostate cancer

Bicalutamide

binds to AR (via H-bonds) but doesn’t cause conformational change

acts as competititve inhibitor

bicalutamide complex is internalised but cannot be translocated to the nucleus

some agonist activity especially at mutant AR

Abiraterone

selective inhibitor of CYP17A1

prevents conversion of progesterone to 17a hydroxyprogesterone (intermediate before androtenedione)

Gefitinib

ATP-competitive inhibitor of EGFR kinase domain which is licenced in Europe as a first line therapy for NSCLC for patients with EGFR mutations

Aminopterin

folate antagonist

folate deficiency helped patients with cancer get better

provided TEMPORARY remission in trials

Methotrexate

Inhibits DHFR at the folate binding site

very potent competitive inhibitor

often used in high dose regimen for folate rescue in normal cells and widely used for cancer

Pyrimethamine

Lipophillic antifolates

inhibits DHFR in many species

used atm as antibacterial

Methylbenzoprim

very potent experimental lipophilic inhibitor of DHFR

Piritrexim

Potent lipophillic inhibitor of DHFR and active in several tumour types

Nolatrexed

Inhibits DHFR and TS and is active against liver carcinoma

Azacytidine

weak inhibitor of TS

phosphorylated to form azacytidine TP the incorporated into RNA and mimics C in RNA but it’s unstable so it decomposes and causes damage to RNA

inhibits DNA methyltransferase

Tiazofurine

Experimental drug

converted to TAD

mimics NAD+

Fludarabine

sugar modified nucleoside

converted to triphosphate

inhibits FNA polymerase as an analogue of dATP

Gemcitabine

blcoks CTP synthase and ribonucleotide reductase which are needed to convert UTP → CTP and CTP→ dCTP respectively

dCTP is a negative feedback loop inhibitor of dCK so less dCTP means mroe dCK which means more F2dCMP from gemcitabine

herceptin/ trastuzumab

HER2 +ve cancer treatment

Goserelin

gonadotropin-releasing hormone (GnRH) agonists, which are also known as luteinizing hormone-releasing hormone (LH-RH) agonists

block ovarian function

Anastrozole

Aromatase inhibitors

block the activity of aromatase which is used in the body to make oestrogen in the ovaries and other tissue

temporary block - post menopausal

Exemestane

Aromatase inhibitors

block the activity of aromatase which is used in the body to make oestrogen in the ovaries and other tissue

permanent block

Tamoxifen

selective oestrogen receptor modulators

bind to oestrogen receptors and prevent oestrogen from binding

treat HR+ hormone receptor–positive breast cancer.

Fulvestrant

Also blocks oestrogen effects

oestrogen antagonist like SERM BUT no agonist effects

pure antioestrogen

when it binds to ER, it targets the receptor for destruction

Palbociclib

CDK4/6 inhibitor

targeted therapy used in combination with letrozole as initial therapy for the treatment of hormone receptor–positive, HER2-negative advanced breast cancer in postmenopausal women.

Lapatinib

tyrosine kinase inhibitor

targeted therapy drug used in combination with aromatase inhibitor to treat HER-positive metasatic breast cancer in postmenopausal women

Paclitaxel

Taxane ligands

isolated from pacific yew trees

Acts to strengthen lateral contacts between adjacent protfilaments – leads to MT stabilisation

Exact mode is compound specific

targets ovarian, mammary and lung tumours

Vinorelbine

semi-synthetic analoges of 1st gen vinca alkaloids

Eribulin

fully synthetic analogue of a marine natural product (halichondrin B)

Mainly binds with high affinity to the (+) end of existing microtubules

Used in metastatic breast cancer and for unresectable liposarcoma

Colchicine

Has been used clinically for treating gout

Severe toxicity at doses required for anti-tumour effects

Slow binding, practically irreversible

Binding to the heterodimer stabilises it in the curved conformation (so it can’t straighten again)

during polymerisation the ends transition from curved at the tip, to straight in the body but presence of a colchicine type ligand prevents this, inhibiting polymerisation

aflibercept

decoy receptor drugs - binds to VEGF

sorefenib

tyrosine kinase inhibitor

sunitinib

tyrosine kinase inhibitor

Denosumab

Target bone resorption - upregualtes RANKL to activate osteoclasts and cause bone resorption

Gleevac

• Imatinib

• first signal transduction inhibitor to fully enter clinic

• A small molecule inhibitor that blocks the activity of Abl tyrosine kinase, used to treat CML.

Dasatinib

second-generation small molecule inhibitor that binds to the active conformation of BCR-abl.

Rituximab

chimeric antibodies - 2nd gen

still immunogenic as ~30% mouse structure

significantly less immune response than 1st gen

safe

Gendicine

• recombinant andenovirus with p53

• used to treat head and neck cancer

Kymriah

• for b-cell lymphocytic leukemia in children and young adults

• recognises CD19

IMLYGIC

• HSV-1 engineered to be oncolytic

• kills cancer and doesn’t harm healthy cells

• it attracts cells of immune system to help fight the leukemia

Abemaciclib

• cdk 4/6 inhibitor

• given alongside endocrine treatment

• used to double the effect of treatment in metastatic setting

Pertuzumab

• anti-HER2

• dimerisation ibhibitor

• improves PFS (progression free survival) alongside docetaxel/trastuzumab in 1st line

NACT with pembrolizumab

Neoadjuvant chemo therpay with pembrolizumab

used to treat triple negative breast cancer

seen a higher PCR (pathological complete response)

Trastuzumab Deruztecan

Her 2 antibody + molecule of chemotherapy attached via linker molecule

targeted chemotherapy so reduced generalised chemo toxicity

Sacituzumab govetican

Used in triply negative/hormone postive cancers

antibody conjugate: trop-2 antibody + topoisomerase inhibitor

used for advanced breast cancer after 2 or more therapies with at least one of them being intended for advanced disease

Pemetrexed

• used to tackle folate pathway

• better overal survival for adenocarcinoma to 12.9months from 10.6 monthscrizotinib

crizotinib

Tyrosine kinase inhibitors

block the activity of the ALK fusion protein, which drives cancer cell growth and survival