. Author manuscript; available in PMC: 2021 May 1.

Published in final edited form as: Drug Discov Today. 2020 Feb 14;25(5):837–850. doi: 10.1016/j.drudis.2020.02.002

Table 3.

Evidence summary for structure-guided drug discovery (SGDD) of LMW-NMEs approved 2010–2018

Generic drug name	Sponsor company	Target protein class	Target protein	Earliest >95% identical target (domain) PDB ID/year	FDA approval year	Target LMW-NME complex PDB ID	Source of target–drug complex PDB ID (Academia, industry)	SGDD (Yes, Prob, Poss, Unl, Nat Prod)
Vemurafenib^a	Roche	Kinase	BRAF	1uwh/2004 [83]	2011	3og7 [43]	Industry	Yes
Dabrafenib^a	GSK	Kinase	BRAF	“	2013	4xv2 [34]	Industry	Yes
Encorafenib^a	Novartis	Kinase	BRAF	“	2018			Yes
Vandetanib	AstraZeneca	Kinase	VEGFRs	1vr2/1999 [116]	2011	2ivu [49]	Academia	Prob
Axitinib	Pfizer	Kinase	VEGFRs	“	2012	4ag8 [38]	Industry	Yes
Lenvatinib	Esai	Kinase	VEGFRs	“	2015	5zv2 [29]	Industry	Yes
Bosutinib	Pfizer	Kinase	SRC	1fmk/1997 [117]	2012	4mxo[48]	Academia	Prob
Regorafenib	Bayer	Kinase	KIT	1pkg/2003 [118]	2012			Poss
Ponatinib	Ariad	Kinase	T315I ABL	1iep/2001 [119]	2012	3ik3[44]	Academia/industry	Yes
Neratinib	Puma	Kinase	EGFRs	1m14/2002 [120]	2017	2jiv [121]	Academe	Prob
Dacomitinib	Pfizer	Kinase	EGFRs	“	2018	4i23 [37]	Industry	Yes
Osimertinib	AstraZeneca	Kinase	EFGRs	“	2015	4zau [47]	Academia	Prob
Afatinib	Boehringer Ingelheim	Kinase	EGFRs	“	2013	4g5j [39]	Industry	Yes
Crizotinib	Pfizer	Kinase	ALK	2yt2/2007 [122]	2011	2xp2 [41]	Industry	Yes
Ceritinib	Novartis	Kinase	ALK	“	2014	4mkc [36]	Academia/industry	Yes
Alectinib	Roche	Kinase	ALK	“	2015	3aox [42]	Industry	Yes
Brigatinib	Ariad	Kinase	ALK	“	2107	6mx8 [33]	Industry	Yes
Lorlatinib	Pfizer	Kinase	ALK	“	2018	4cli [46]	Industry	Yes
Palbociclib	Pfizer	Kinase	CDK4/6	1bi8/1998 [76]	2015	5l2i [31]	Industry	Yes
Ribociclib	Novartis	Kinase	CDK4/6	“	2017	5lt2 [31]	Industry	Yes
Abemaciclib	Lilly	Kinase	CDK4/6	“	2017	5l2s [31]	Industry	Yes
Cobimetinib	Exelixis	Kinase	MEK	1s9j/2004 [90]	2015	4an2 [40]	Industry	Yes
Binimetinib	Array Biopharma	Kinase	MEK	“	2018			Yes
Trametinib^a	JapanTobacco	Kinase	MEK	“	2013			Poss
Cabozantinib	Bristol Myers Squibb	Kinase	MET	1r0p/2003 [123]	2016	3lq8 [45]	Industry	Yes
Idelalisib	Gilead	Kinase	PI3Ks	2rd0/2007 [124]	2014	4xe0 [35]	Industry	Yes
Copanlisib	Bayer	Kinase	PI3Ks	“	2017	5g2n [32]	Industry	Yes
Duvelisib	Intellikine	Kinase	PI3Ks	“	2018			Poss
Ibrutinib	Celera	Kinase	BTK	1btk/1997 [125]	2013	5p9i [30]	Industry	Yes
Acalabrutinib	Acerta	Kinase	BTK	“	2017			Yes
Larotrectinib	Array Biopharma	Kinase	TRKs	5jfw/2016 [126]	2018			Poss
Gilteritinib	Astellas	Kinase	FLT3	1rjb/2004 [127]	2018	6jqr [28]	Industry	Yes
Ivosidenib	Agios	Enzyme	IDH1	1t09/2004 [128]	2018			Yes
Enasidenib^a	Agios	Enzyme	IDH2	1lwd/2002 [77]	2017	5i96 [50]	Industry	Yes
Venetoclax	Abbott	Programmed cell death	BCL-2	1g5m/2000 [129]	2016	6o0k [51]	Industry	Yes
Olaparib	AstraZeneca	Enzyme	PARPs	1uk0/2004 [130]	2014	4tvj [52]	Academia	Prob
Rucaparib	Clovis Oncology	Enzyme	PARPs	“	2016	4rv6 [52]	Academia	Prob
Niraparib	GSK	Enzyme	PARPs	“	2017	4r6e [52]	Academia	Prob
Talazoparib	Pfizer	Enzyme	PARPs	“	2018	4und [52]	Academia	Prob
Enzalutamide	Medivation	Nuclear hormone receptor	Androgen receptor	1e3g/2000 [131]	2012			Prob
Apalutamide	Janssen	Nuclear hormone receptor	Androgen receptor	“	2018			Prob
Belinostat	Spectrum Pharmaceuticals	Epigenetic	HDACs	1t64/2004 [132]	2014	5een [53]	Academia	Prob
Panobinostat	Novartis	Epigenetic	HDACs	“	2015	5ef8 [53]	Academia	Prob
Vismodegib	Roche	GPCR	Smoothened	4jkv/2013 [132]	2012	5l7i [133]	Academia	Unl
Sonidegib	Sun Pharma	GPCR	Smoothened	“	2015			Unl
Glasdegib	Pfizer	GPCR	Smoothened	“	2018			Unl
Abiraterone acetate	Apotex	Cytochrome P450	CYP17A1	3ruk/2012 [134]	2011	3ruk [134]	Academia	Unl
Pomalidomide	Celgene	Protein degradation	E3 ubiquitin ligase	2hye/2006 [135]	2013	6h0f [136]	Academia	Unl
Ixazomib citrate	Millennium	Protein degradation	Proteasome	4r3o/2015 [137]	2015	5lf7 [138]	Academia	Unl
Carfilzomib	Amgen	Protein degradation	Proteasome	“	2012	4r67 [137]	Academia	Nat Prod
Cabazitaxel	Sanofi-Aventis	Cell division	Tubulin	1z5v/2005 [139]	2010			Nat Prod
Eribulin	Eisaai	Cell division	Tubulin	“	2010			Nat Prod
Omacetaxine mepesuccinate	Teva	Ribosome	A site	3j7y/2014 [140]	2012	3g6e [141]	Academia	Nat Prod
Midostaurin	Millennium	Kinase	Multiple kinases	N/A	2017	4nct [142]	Academia	Nat Prod

Indicates LMW-NMEs featured in the three case studies described at the end of this review.

Abbreviations: VEGFR, vascular endothelial growth factor receptor; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; PI3K, phosphoinositide 3-kinase; BTK, Bruton’s tyrosine kinase; TRK, tropomyosin receptor kinase.