Drug Class and Agent Flashcards
Proteasome
Inhibitors
Bortezomib (Velcade)
Carfilzomib (Kyprolis)
Ixazomib (Ninlaro )
MOA of Proteasome Inhibitor
Inhibitions of the proteasome and aggresome pathways by bortezomib and deacetylase inhibitors (DACi). Unfolded/misfolded proteins are targeted by ubiquitin for degradation by the proteasome and aggresome pathways. The proteasome inhibitor bortezomib leads to the accumulation of ubiquitin protein aggregates. These aggregates are shuttled to the lysosome, where they are degraded via the aggresome pathway. Aggresome formation involves the shuttling of the protein aggregates along microtubules by dynein motor proteins. The interaction of the unfolded/misfolded protein complexes is facilitated by histone deacetylase 6 (HDAC6). Conversely, DACi with inhibitory activity toward HDAC6 block this process. The combination of proteasome inhibitors and DACi lead to increased cellular stress and apoptosis.
What is BTK inhibitors MOA ?
BTK is an essential component of B-cell receptor (BCR) signaling
Unregulated BCR signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL)
MOA :
Bruton’s tyrosine kinase (BTK) inhibitors work by binding to the BTK protein. BTK inhibitors block this protein’s activity by the BCR-induced BTK activation and its downstream signalling. BTK inhibitors block the activity that leads to growth of the B-cells and this causes cell death of the malignant B-cells.
BTK Inhibitors
Acalabrutinib (Calquence)
Ibrutinib (Imbruvica)
Zanubrutinib (Brukinsa)
BTK inhibitor stand for
Bruton Tyrosine Kinase Inhibitors
BCR-ABL TKIs
Bosutinib (Bosluif)
Dasatinib (Tasigna)
Imatinib (Glivec)
Nilotinib (Tasigna)
Ponatinib (Iclusig)
MOA of BCR-ABL TKI’s
MOA :
As a whole, tyrosine kinases phosphorylate specific amino acids on substrate enzymes, which subsequently alter signal transduction leading to downstream changes in cellular biology. The downstream signal transduction set off by TKs can modify cell growth, migration, differentiation, apoptosis, and death. Constitutive activation or inhibition, either by mutations or other means, can lead to dysregulated signal cascades, potentially resulting in malignancy and other pathologies.[4][40] Therefore, blocking these initial signals via TKIs can prevent the aberrant action of the mutated or dysfunctional TKs.
PI3K Inhibitors
Copanlisib (Aliqopa)
Duvelisib (Copiktra)
Idelalisib (Zydelig)
Umbralasib (Ukoniq)
PI3K Inhibitors MOA
MOA:
Copanlisib -Follicular lymphoma is a B-cell lymphoma that is one of the most common type of non-Hodgkin lymphoma (NHL). It involves unregulated growth and proliferation of lymphocytes that eventually may travel to other organs including the lymph nodes, spleen, and the bone marrow, to form tumors. The phosphatidylinositol 3-kinase (PI3K)-mediated pathway is involved in promoting cell survival proliferation and differentiation however abberant activation of this pathway may lead to tumorigenesis 1. Copanlisib mediates an inhibitory action on p110α and p110δ isoforms of phosphatidylinositol-3-kinase (PI3K) expressed in malignant B cells. It induces tumor cell death via apoptosis and inhibits the proliferation of primary malignant B cell lines Label. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines
Duvelisib -PI3K-δ inhibition prohibits proliferation and reduces viability in malignant B cells
JAK Inhibitors
Ruxolitinib (Jakafi)
MOA of JAkafi
JAKAVI acts on both JAK1 and JAK2 to inhibit overactive JAK/STAT signalling in MF[1]
JAKAVI binds to the kinase domain of JAK1 and JAK2 and inhibits JAK1 and JAK2 signalling regardless of the JAK2V617F mutation status[1]
JAKAVI inhibits JAK stimulation of STAT and downstream effects on cellular proliferation[1]
IDH1 & IDH2
Inhibitors
Enasidenib
Ivosidenib (Tibsovo)
What is Differntiation syndrome
Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased
Indication for Ivosidenib ( Tibsovo)
Ivosidenib is approved to treat adults whose cancer has a certain mutation in the IDH1 gene, including:
Acute myeloid leukemia (AML). It is used:
Alone or with azacitidine in patients with newly-diagnosed cancer who are aged 75 years and older or who, due to health problems, cannot receive intensive induction chemotherapy.
When the cancer has come back or has not gotten better after previous treatment.
Cholangiocarcinoma (bile duct cancer) that has spread. It is used in adults whose cancer has been treated.
Test for IDH1 mutations at diagnosis so you can offer targeted therapy to appropriate patients
1.Patients without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during treatment and at relapse
2.In the pivotal trials, IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime™ IDH1 assay, which is the FDA-approved test for selection of patients with AML for treatment with TIBSOVO7
3.Both the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) and ASH‑CAP Guidelines recommend testing for IDH1 mutations in patients with AML6,8
4.NCCN Guidelines® recommend ivosidenib (TIBSOVO) + azacitidine as a category 1 preferred treatment option for newly diagnosed patients ≥60 years of age with mIDH1 who are not candidates for intensive remission induction therapy8
5.NCCN Guidelines recommend ivosidenib (TIBSOVO) monotherapy for IC-ineligible newly diagnosed and R/R AML patients with an IDH1 mutation8
