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Crenolanib Is a Selective Type I Pan-FLT3 Inhibitor

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Crenolanib Is a Selective Type I Pan-FLT3 Inhibitor Crenolanib is a selective type I pan-FLT3 inhibitor Catherine Choy Smitha,b,1, Elisabeth A. Lasatera,1, Kimberly C. Lina, Qi Wangc, Melissa Quino McCreeryd, Whitney K. Stewarta, Lauren E. Damona, Alexander E. Perle, Grace R. Jeschkee, Mayumi Sugitae, Martin Carrolle, Scott C. Koganb,d, John Kuriyanc, and Neil P. Shaha,b,2 aDivision of Hematology/Oncology, bHelen Diller Family Comprehensive Cancer Center, and dDivision of Laboratory Medicine, University of California, San Francisco, CA 94143; cDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; and eDivision of Hematology/Oncology, Perelman School of Medicine and the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104 Edited* by Charles L. Sawyers, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved February 13, 2014 (received for review November 4, 2013) Tyrosine kinase inhibitors (TKIs) represent transformative thera- inhibitor and holds significant promise for achieving prolonged pies for several malignancies. Two critical features necessary for remissions. However, ponatinib potently inhibits a number of maximizing TKI tolerability and response duration are kinase selec- kinases, which may be responsible for unanticipated serious tivity and invulnerability to resistance-conferring kinase domain (KD) cardiovascular toxicities that have emerged with this agent. mutations in the intended target. No prior TKI has demonstrated The ability to selectively suppress resistance-conferring muta- both of these properties. Aiming to maximize selectivity, medicinal tions remains a highly desirable quality that no TKI has yet chemists have largely sought to create TKIs that bind to an inactive demonstrated. (type II) kinase conformation. Here we demonstrate that the inves- Internal tandem duplication (ITD) mutations in the class III tigational type I TKI crenolanib is a potent inhibitor of Fms tyrosine receptor tyrosine kinase (RTK) Fms tyrosine kinase-3 (FLT3) – ∼ kinase-3 (FLT3) internal tandem duplication, a validated therapeutic juxtamembrane domain (FLT3 ITD) occur in 30% of acute target in human acute myeloid leukemia (AML), as well as all myeloid leukemia (AML) patients (6), and are associated with secondary KD mutants previously shown to confer resistance to the poor outcomes. An additional subset of AML patients has acti- first highly active FLT3 TKI quizartinib. Moreover, crenolanib is highly vating point mutations within the activation loop (AL) of FLT3 (7) that presumably stabilize an active (type I) kinase confir- selective for FLT3 relative to the closely related protein tyrosine – kinase KIT, demonstrating that simultaneous FLT3/KIT inhibition, mation. Although initial attempts to target FLT3 ITD with first- generation TKI monotherapy were largely unsuccessful (8, 9), a prominent feature of other clinically active FLT3 TKIs, is not required MEDICAL SCIENCES for AML cell cytotoxicity in vitro and may contribute to undesirable the highly potent second-generation TKI quizartinib (AC220), toxicity in patients. A saturation mutagenesis screen of FLT3–internal which primarily targets FLT3, KIT, and RET in the inactive tandem duplication failed to recover any resistant colonies in the (type II) conformation, has recently demonstrated clearance of bone marrow blasts in a large proportion of chemotherapy-re- presence of a crenolanib concentration well below what has been – + safely achieved in humans, suggesting that crenolanib has the po- sistant FLT3 ITD AML patients (10, 11). Moreover, the demonstration that drug-resistant point mutations in the KD of tential to suppress KD mutation-mediated clinical resistance. Creno- FLT3–ITD evolve at the time of relapse on quizartinib has for- lanib represents the first TKI to exhibit both kinase selectivity and mally validated FLT3–ITD as a therapeutic target (12) and invulnerability to resistance-conferring KD mutations, which is un- rekindled interest in developing potent FLT3 inhibitors. To date, expected of a type I inhibitor. Crenolanib has significant promise for clinically relevant quizartinib-resistant KD mutations in FLT3– achieving deep and durable responses in FLT3–mutant AML, and ITD are restricted to amino acids F691 and D835 (12). F691 may have a profound impact upon future medicinal chemistry efforts represents the “gatekeeper” position in FLT3, analogous to in oncology. sorafenib | activation-loop mutations | D835 mutations Significance Rapid evolution of drug resistance associated with secondary ioneering studies demonstrated that imatinib, the first small kinase domain (KD) mutations is the best characterized mech- molecule tyrosine kinase inhibitor (TKI), binds to an inactive P anism of acquired resistance to effective tyrosine kinase in- kinase conformation of the Abelson protein tyrosine kinase (ABL) hibitor (TKI) therapy. Medicinal chemistry efforts have largely (1). Compounds that bind to kinases in this manner have been “ ” “ ” been devoted toward synthesizing type II TKIs that, by tar- termed type II ,whereas type I inhibitors bind to an active geting an inactive kinase conformation, are believed to afford conformation. Type II inhibitors typically target the ATP binding greater selectivity than type I TKIs that bind an active kinase region and an adjacent allosteric site available only in an inactive conformation. The only previously described TKI with the ability conformation. Because this region is less well conserved among to successfully suppress all resistance-conferring KD mutants kinases than the ATP binding region, interactions with this area (i.e. “pan-kinase” inhibitor) is the type II multikinase TKI pona- allow for greater selectivity. tinib. Here, we demonstrate that a type I TKI can be potent, Despite the clinical success of imatinib for the treatment of selective, and invulnerable to resistance-conferring KD mutation chronic myeloid leukemia (CML), durability of response is com- as a mechanism of resistance. Efforts to develop potent, selec- – promised by secondary kinase domain (KD) mutations in BCR tive type I pan-kinase inhibitors are warranted. ABL (1), many of which destabilize the inactive conformation re- quired for imatinib binding (1). Second-generation ABL inhibitors, Author contributions: C.C.S., E.A.L., Q.W., A.E.P., M.C., S.C.K., J.K., and N.P.S. designed dasatinib (type I) and nilotinib (type II), were subsequently de- research; C.C.S., E.A.L., K.C.L., Q.W., M.Q.M., W.K.S., L.E.D., A.E.P., G.R.J., and M.S. per- veloped to retain efficacy against most imatinib-resistant BCR–ABL formed research; C.C.S., E.A.L., K.C.L., Q.W., A.E.P., J.K., and N.P.S. analyzed data; and KD mutants, and each are vulnerable to only approximately five C.C.S., E.A.L., Q.W., and N.P.S. wrote the paper. resistance-conferring mutations (2, 3). In contrast, the third-gener- The authors declare no conflict of interest. ation type II inhibitor ponatinib has proven largely invulnerable to *This Direct Submission article had a prearranged editor. single nucleotide resistance-conferring KD mutations in vitro (4), 1C.C.S. and E.A.L. contributed equally to this work. and no single nucleotide substitution within BCR–ABL has 2To whom correspondence should be addressed. E-mail: [email protected]. been associated with acquired resistance in patients (5). There- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. fore, ponatinib has justifiably been termed a “pan-BCR–ABL” 1073/pnas.1320661111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1320661111 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 residues in other kinases that are hotspots for drug-resistance to ABHB1119 Molm14 TKIs (both type I and type II), such as BCR–ABL/T315 (1). Mutations at D835 within the FLT3 AL have been found in the majority of FLT3–ITD+ AML patients with acquired resistance to Untreated Untreated quizartinib. These substitutions are postulated to destabilize the Crenolanib Crenolanib inactive conformation required for efficient binding by type II TKIs pFLT3 tFLT3 such as quizartinib. Analogous substitutions in KIT (KIT/D816V) IP: FLT3 and platelet-derived growth factor receptor (PDGFR) (PDGFR/ pERK D842V)conferahighdegreeofresistancetotypeIITKIs(13,14). tERK Although a number of potent second-generation type II FLT3 MV4-11 #2830 #1727 TKIs are currently undergoing clinical development for the treat- C ment of AML and/or have reported single agent activity (e.g., pFLT3 sorafenib) (15), these agents, including the pan-BCR–ABL in- tFLT3 IP: FLT3 IP: FLT3 hibitor ponatinib, which has potent activity against FLT3, are uniformly ineffective at inhibiting quizartinib-resistant FLT3– D Molm14 parental Molm14-D835Y ITD/D835 mutants (12, 16). These data suggest that a type I – FLT3 TKI will be required to effectively inhibit FLT3 ITD/D835 0 nM 10 nM 50 nM 100 nM 500 nM 1000 nM 0 nM 10 nM 50 nM 100 nM 500 nM 1000 nM mutants. However, previous monotherapy clinical experience with pFLT3 (4G10) type I FLT3 TKIs midostaurin and lestaurtinib demonstrated IP: FLT3 IP: FLT3 tFLT3 minimal clinical activity (8, 9), presumably due to a lack of selec- tivity resulting in dose-limiting toxicities that preclude potent pSTAT5 FLT3 inhibition. tSTAT5 Crenolanib is an investigational TKI that was initially de- pS6 veloped as a highly selective PDGFR inhibitor (17). A phase I tS6 study documented the safe achievement of low micromolar trough plasma concentrations without significant myelosuppression (17), Fig. 1. Activity of crenolanib
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