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kinetics, whereas neratinib is an irreversible covalent catalyze the conversion of isocitrate to α-ketoglutarate but
inhibitor.312−314 instead gains the ability to catalyze the NADPH-dependent
Historically, small molecule inhibitors have been more reduction of α-ketoglutarate to (R)-2-hydroxyglutarate (2HG).
successful in targeting HER2 mutations than monoclonal This observation has been further supported by X-ray
antibodies, with reports that activating mutations of HER2 are structural studies. For this reason significant small molecule
sensitive to neratinib, but not lapatinib.315 However, some drug discovery efforts have been carried out against IDH1 and
HER2 mutations have shown greater sensitivity to ADCs such IDH2, most notably by Agios Pharmaceuticals with their
as trastuzumab emtansine and DS-8201.316,317 There are inhibitors ivosidenib (AG-120, IDH1 mutant)325 and
relatively few HER2 X-ray crystal structures with small enasidenib (AG-221, IDH2 mutant)326 approved by the
molecules bound in the Protein Data Bank; one example is FDA for the treatment of AML in the past few years (Figure
shown in Figure 47. A consistent feature of these inhibitors is 48). Such compounds are also being evaluated in solid tumors
that they contain elongated groups which bind into the back such as glioma and cholangiocarcinoma.
pocket of the kinase in the c-helix out conformation.
Resistance mechanisms have been observed in HER2-based
therapies, although much of this data is from the treatment of
breast cancer, and differences may be observed across disease
indications. As one example, NSCLC in general has a higher
prevalence of brain metastases as a mechanism of resistance to
drug treatment.318 Intrinsic mechanisms of resistance to HER2
therapy appear to include PI3K pathway alterations which
include PTEN loss and PIK3CA mutations and loss of the
antibody binding epitope. The activation of the RAS/RAF
pathway has also been implicated, which has led to subsequent
combination studies with additional agents. The emergence of Figure 48. FDA approved IDH1 and IDH2 inhibitors.
gatekeeper mutants in HER2 (T798I and T798M) has also
been reported from small molecule inhibition, such as lapatinib Mechanisms of resistance have been reported to IDH1
and neratinib.319,320 Which of these mechanisms of resistance agents during clinical evaluation and highlighted in several case
are observed clinically will vary depending on the disease being studies. In vitro biochemical studies had speculated that
treated and the agent being used, both of which are rapidly resistance to IDH inhibitors could be observed via mutations
evolving in the HER2 space. It will take therefore take time to at the dimer interface; this was confirmed in a patient being
understand the optimal sequence of these therapies in their treated with the IDH1 inhibitor ivosidenib.327 In addition, two
respective diseases. patients were studied who had shown a clinical response,
Alternative approaches to target HER2 include novel agents followed by resistance, to treatment with enasidenib. It was
such as ZW25 and MP0274, which may have the potential to shown that the resistance was driven by second-site mutants
target different patient populations or emerging resistance. Q316E and I319M which are at the dimer interface where
ZW25321 is a biparatropic antibody targeting two HER2 enasidenib binds. Additional case studies have been reported
epitopes, whereas MP0274322 is a designed ankytun repeat which highlight the potential for IDH isoform switching as an
protein (DARPin) targeting HER2. There is also a range of additional mechanism of resistance.328 Two patients who had
combinations among HER2-targeted agents and combination shown a clinical response with ivosidenib in acute myeloid
with chemotherapies and endocrine therapies being evaluated. leukemia (AML), followed by relapse, showed an increase in
Inhibitors of the PI3K/AKT/mTOR pathway have also been blood HG levels and appearance of IDH2 R140Q mutations,
combined with HER2 agents. while a third showed a IDH2 R172V mutation. Alternatively, a
Additional small molecule inhibitors have been reported patient with an IDH2 R140Q mutation under treatment with
including tucatinib, which has much improved selectivity over enasidenib showed disease progression through the emergence
EGFR wild type compared to previous small molecule of IDH1 R132C.
inhibitors.323 This inhibitor was granted breakthrough Additional IDH1 and IDH2 inhibitors are under clinical
designation therapy in December 2019 based on combination evaluation in an attempt to improve or provide alternative
data with trastuzumab and capecitabine in patients with treatments to the currently approved agents (Figure 49).329
unresectable locally advanced or metastatic HER2-positive Vorasidenib (AG-881) was subsequently designed as a dual
breast cancer. Poziotinib and AP32788/TAK-788 are also IDH1 and IDH2 mutant inhibitor to avoid potential resistance
being evaluated as HER2-targeting agents in clinical trials, in mechanisms from mutations along with improved blood−brain
both breast and NSCLC, with some evidence of clinical barrier permeability to target glioma.330 Further compounds
efficacy reported.273 have entered clinical development, such as IDH-305
(Novartis), which is a brain penetrant IDH1 inhibitor in
3.14. IDH
phase I clinical trials for the treatment of advanced
IDH1 and IDH2 mutations are frequently observed in grade malignancies that harbor IDH1 R132 mutations.331 Olutasi-
II−III human gliomas and secondary gliomas with a frequency denib (Forma Therapeutics) is being evaluated in phase I trials
of around 80%.324 In addition, mutations in IDH1 and IDH2 for the treatment of patients with AML or myelodysplastic
are commonly observed in a subset (∼20%) of acute syndrome with an IDH1 mutation, as a single agent or in
myelogenous leukemia (AML). This key mutation is located combination with azacitidine. The company is also evaluating
at Arg-132 in IDH1, of which the most common mutation is the product in early clinical developments for the treatment of
R132H (corresponding to R140 or R172 in IDH2). The patients with advanced IDH1 R132 gene-mutated solid tumors
impact of this mutation is that the enzyme loses its ability to and gliomas, as a single agent or in combination studies.332
AJ https://dx.doi.org/10.1021/acs.chemrev.0c00383
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