Discovery of 3-[2-(Imidazo[1,2-<i>b</i>]pyridazin-3-yl)ethynyl]-4-methyl-<i>N</i>-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant

Huang, Wei‐Sheng; Metcalf, Chester A.; Rajeswari, S.; Wang, Yihan; Zou, Da; Thomas, R. M.; Zhu, Xiaotian; Cai, Lixin; Wen, David; Liu, Shuangying; Romero, Jan Antoinette C.; Qi, Jiwei; Chen, Ingrid; Banda, Geetha; Lentini, Scott; Das, Sasmita; Xu, Qihong; Keats, Jeff; Wang, Frank; Wardwell, Scott; Ning, Yaoyu; Snodgrass, J. T.; Broudy, Marc I.; Russian, Karin; Zhou, Tianjun; Commodore, Lois; Narasimhan, Narayana I.; Mohemmad, Qurish K.; Iuliucci, John D.; Rivera, Victor M.; Dalgarno, David C.; Sawyer, Tomi K.; Clackson, Tim; Shakespeare, William C.

doi:10.1021/jm100395q

Cited by 333 publications

(240 citation statements)

References 49 publications

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“…We recently reported the design and preclinical evaluation of ponatinib (Table 1), a potent inhibitor of native BCR-ABL, BCR-ABL T315I , and other resistant mutants (IC 50 : 0.5-36 nM) (53)(54)(55). Ponatinib inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL T315I -driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens, confirming its profile as a pan-BCR-ABL inhibitor.…”

Section: Targeting the Bcr-abl T315i Mutant: Clinical Candidatesmentioning

confidence: 99%

Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia

O’Hare

Deininger

Eide

et al. 2011

Clinical Cancer Research

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Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABL T315I . A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABL T315I . The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABL T315I mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL T315I in the development pipeline.

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Section: Targeting the Bcr-abl T315i Mutant: Clinical Candidatesmentioning

confidence: 99%

Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia

O’Hare

Deininger

Eide

et al. 2011

Clinical Cancer Research

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130

104

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“…Finally, dovitinib (TKI258) inhibits the kinase activity of FGFR1, FGFR2, and FGFR3 and the cellular activity of FGFR3 in models of multiple myeloma (34,35). Ponatinib (AP24534) is an oral multitargeted kinase inhibitor that potently inhibits native and mutant forms of BCR-ABL (36)(37)(38) and is currently being investigated in a phase II pivotal trial in patients with chronic myelogenous leukemia (CML; Clinicaltrials.gov: NCT01207440). Initial characterization of the kinase selectivity profile of ponatinib showed that it exhibits potent in vitro biochemical activity, with IC 50 values <20 nmol/L, against 40 additional kinases including all 4 FGFRs (37).…”

Section: Introductionmentioning

confidence: 99%

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

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Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC 50 values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC 50 values <40 nmol/L and inhibited cell growth with GI 50 (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL-driven models and plasma levels of ponatinib that exceed the IC 50 values for FGFR1-4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers.

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“…The following two cases illustrate how it can steer property‐based lead optimization to improve pharmacokinetics. The first example is the optimization of third‐generation BCR‐ABL kinase inhibitors, starting from the lead BCR‐ABL‐1 with poor pharmacokinetics, distant from the egg, to finally obtain the oral anticancer drug ponatinib 20. Ponatinib correctly lies inside the white ellipse, but inside the BOILED‐Egg′s yolk, too (blue path in Figures 2 b and S9).…”

mentioning

confidence: 99%

A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

2016

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Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED‐Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED‐Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.

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Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant

Cited by 333 publications

References 49 publications

Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia

Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

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